Pyrazole derivative

ABSTRACT

Provided is a novel therapeutic means for Alzheimer&#39;s disease. 
     In particular, provided is a compound represented by the following general formula (I): 
                         
or
 
a salt thereof.

TECHNICAL FIELD

The present invention relates to a novel compound; a tau protein(hereinafter also referred to as tau) aggregation inhibitor, aβ-secretase inhibitor, and a β-amyloid protein (hereinafter alsoreferred to as Aβ) aggregation inhibitor using the same; and a novelpyrazole derivative useful for the prevention or treatment of diseasessuch as dementia and Alzheimer's disease and a pharmaceuticalcomposition containing the same.

BACKGROUND ART

Senile dementia has become a serious medical and social problem alongwith the rapid aging of society in recent years and the development ofeffective anti-dementia drugs has been greatly desired. There arealready very many studies on Alzheimer's disease but the cause of thedisease has not been clearly defined. Drugs such as acetylcholinesteraseinhibitors including donepezil (Aricept (registered trademark)),galantamine (Reminyl) and rivastigmine (Exelon/Rivastach), and NMDAreceptor antagonists including memantine hydrochloride (Memary) havebeen used as Alzheimer's therapeutic drugs. These drugs are very usefulas symptomatic therapy but are not drugs for fundamental treatment.

Alzheimer's disease is considered to be caused by aggregation of Aβ,aggregation of tau, and the like. Hence, a substance that inhibitsaggregation of these proteins could be used as a fundamental therapeuticdrug for Alzheimer's disease.

Yang et al. have reported that curcumin has an Aβ aggregation inhibitoryactivity, a disaggregation activity on Aβ aggregate, and the like (NonPatent Literature 1). The inventors of the present invention haverevealed that curcumin and its derivatives have an inhibitory activityagainst secretase, which is involved in the generation of Aβ (PatentLiterature 1 and 2). Narlawar et al. have synthesized curcuminderivatives by replacing the 1,3-dicarbonyl moiety with a pyrazole ringand reported that these compounds have a tau aggregation inhibitoryactivity (Non Patent Literature 2).

CITATION LIST Patent Literature

-   Patent Literature 1: WO 2008/066151-   Patent Literature 2: WO 2009/145219

Non Patent Literature

-   Non Patent Literature 1: Fusheng Yang et al., J. Biol. Chem. 2005,    Feb. 18; 280 (7) 5892-5901-   Non Patent Literature 2: Rajeshwar Narlawar et al., Chem Med Chem    2008, 3, 165-172

SUMMARY OF INVENTION Technical Problem

As described in the above literature, a curcumin derivative can be apromising candidate for a fundamental therapeutic drug for Alzheimer'sdisease. Under this technical background, an object of the presentinvention is thus to provide a novel therapeutic means for Alzheimer'sdisease.

Solution to Problem

The inventors succeeded in creating a novel compound based on technicalideas that are distinct from those forming the basis of known compoundsand found that the compound has an excellent pharmacological activity.The inventors further conducted extensive studies to complete thepresent invention.

That is, as a result of the extensive investigations to solve the aboveproblems, the inventors succeeded in synthesizing a curcumin derivativeby replacing the 1,3-dicarbonyl moiety of curcumin with a pyrazole ringand replacing at least one of the 4-hydroxy-3-methoxyphenyl groups atboth ends with a substituent, and found that this novel compound has apotent tau aggregation inhibitory activity. The inventors also foundthat this derivative has a high brain penetration and also possesses aβ-secretase inhibitory activity and an Aβ aggregation inhibitoryactivity.

A curcumin derivative in which the 1,3-dicarbonyl moiety of curcumin isreplaced with a pyrazole ring is described in Non Patent Literature 2etc. A curcumin derivative in which one of the 4-hydroxy-3-methoxyphenylgroups at both ends of curcumin is replaced with a substituent isdescribed in Patent Literature 1 and 2, etc. However, the derivative ofthe present invention which has a pyrazole ring and in which at leastone of the 4-hydroxy-3-methoxyphenyl groups at both ends is replacedwith a substituent is a novel compound having a chemical structure thatis unique to the present invention and distinct from those of compoundsdisclosed in known literature.

The tau aggregation inhibitory activity of a curcumin derivative isdescribed in Non Patent Literature 2. In this literature, the nitrogenatom at position 1 of the pyrazole ring is replaced with various groups,and the tau aggregation inhibitory activities of the derivativessignificantly vary with the groups introduced into the ring. However, nomodification was made to the benzene rings at both ends and thus all thesynthesized derivatives have the 4-hydroxy-3-methoxyphenyl groups ascurcumin does. Therefore, the person skilled in the art who has read NonPatent Literature 2 is expected to consider that the group introducedinto the pyrazole ring plays an important role for the tau aggregationinhibitory activity and that the 4-hydroxy-3-methoxyphenyl groups atboth ends are irrelevant to the tau aggregation inhibitory activity.Thus the person skilled in the art would not attempt to replace the4-hydroxy-3-methoxyphenyl groups with a substituent.

That is, the present invention relates to the following.

[1] A compound represented by the following general formula (I):

[wherein

R¹ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitrogroup, an amino group, a cyano group, a C₁₋₆ alkyl group optionallyhaving one or more substituents, a C₁₋₆ alkoxy group optionally havingone or more substituents, a mono- or di(C₁₋₆ alkyl)amino groupoptionally having one or more substituents, a C₁₋₆ alkylthio groupoptionally having one or more substituents, a C₁₋₆ alkylsulfonyl groupoptionally having one or more substituents, a C₁₋₆ acyl group optionallyhaving one or more substituents, a C₁₋₆ acylamino group optionallyhaving one or more substituents, a C₂₋₆ alkenyl group optionally havingone or more substituents, a C₂₋₆ alkenyloxy group optionally having oneor more substituents, a mono- or di(C₂₋₆ alkenyl)amino group optionallyhaving one or more substituents, a C₂₋₆ alkenylthio group optionallyhaving one or more substituents, or a carbamoyl group optionally havingone or more substituents;

R² represents a group represented by the following general formula (II):

(wherein m and n each represent an integer of 0 or 1,

A represents —O—, —NH—, —S—, —SO— or —SO₂—,

Y represents a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₂₋₆alkynylene group, and

R³ represents a nitrogen-containing heterocyclic group optionally havingone or more substituents, a C₁₋₆ alkoxy group optionally having one ormore substituents, a mono- or di(C₁₋₆ alkyl)amino group optionallyhaving one or more substituents, a mono- or di(C₂₋₆ alkenyl)amino groupoptionally having one or more substituents, or a carbamoyl groupoptionally having one or more substituents);

R¹ and R² may be joined to form a ring together with the benzene ring;and

Ar represents a homocyclic or heterocyclic group optionally having oneor more substituents],

or a salt thereof.

[2] The compound according to the above [1] or a salt thereof, wherein mis 1 and A is —O—.

[3] The compound according to the above [2] or a salt thereof, whereinR² is a morpholinomethoxy group, a morpholinoethoxy group, apyridylmethoxy group, a pyridylethoxy group, a 2-pyrrolidinoethoxygroup, a 2-piperidinoethoxy group, a 2-(4-(substituted)piperazino)ethoxygroup, or a 2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy group.[4] The compound according to the above [3] or a salt thereof, whereinR² is a morpholinoethoxy group.[5] The compound according to the above [1] or a salt thereof, whereinR² is a morpholinomethyl group, a (4-(substituted)piperazino)methylgroup, a (1,1-dioxo-1,4-thiazinan-4-yl)methyl group, a piperidinomethylgroup, a pyrrolidinomethyl group, a 2-morpholinoethyl group, a2-(4-(substituted)piperazino)ethyl group, a2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl group, a 2-piperidinoethyl group,a 2-pyrrolidinoethyl group, or a 2-morpholinoethanesulfonyl group.[6] The compound according to the above [1] or a salt thereof, whereinR² is a 4-(substituted)piperazino group or a4-(substituted)-1,4-diazepano group, with the exception of the casewhere Ar is a homocyclic group optionally having a substituent.[7] The compound according to any one of the above [1] to [6] or a saltthereof, wherein Ar is a bicyclic group having a benzene skeleton andoptionally having one or more substituents.[8] The compound according to the above [7] or a salt thereof, whereinthe bicyclic group having a benzene skeleton is a 1,3-benzodioxolegroup, a 1,4-benzodioxan-5-yl group, a 1,4-benzodioxan-6-yl group, a1,4-benzodioxin-2-yl group, a quinolino group, or an indolyl group.[9] The compound according to any one of the above [1] to [5] or a saltthereof, wherein Ar is a phenyl group optionally having one or moresubstituents, a pyrrolyl group optionally having one or moresubstituents, a pyridyl group optionally having one or moresubstituents, a pyrazyl group optionally having one or moresubstituents, an imidazolyl group optionally having one or moresubstituents, or a furyl group optionally having one or moresubstituents.[10] The compound according to the above [6] or a salt thereof, whereinAr is a pyrrolyl group optionally having one or more substituents, apyridyl group optionally having one or more substituents, a pyrazylgroup optionally having one or more substituents, an imidazolyl groupoptionally having one or more substituents, or a furyl group optionallyhaving one or more substituents.[11] The compound according to the above [1] or a salt thereof, whereinAr is represented by the following general formula (III):

(wherein

R¹′ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitrogroup, an amino group, a cyano group, a C₁₋₆ alkyl group optionallyhaving one or more substituents, a C₁₋₆ alkoxy group optionally havingone or more substituents, a mono- or di(C₁₋₆ alkyl)amino groupoptionally having one or more substituents, a C₁₋₆ alkylthio groupoptionally having one or more substituents, a C₁₋₆ alkylsulfonyl groupoptionally having one or more substituents, a C₁₋₆ acyl group optionallyhaving one or more substituents, a C₁₋₆ acylamino group optionallyhaving one or more substituents, a C₂₋₆ alkenyl group optionally havingone or more substituents, a C₂₋₆ alkenyloxy group optionally having oneor more substituents, a mono- or di(C₂₋₆ alkenyl)amino group optionallyhaving one or more substituents, a C₂₋₆ alkenylthio group optionallyhaving one or more substituents, or a carbamoyl group optionally havingone or more substituents;

R²′ represents a group represented by the following general formula(IV):

(wherein m′ and n′ each represent an integer of 0 or 1,

A′ represents —O—, —NH—, —S—, —SO— or —SO₂—,

Y′ represents a C₁₋₆ alkylene group, a C₂₋₆ alkenylene group or a C₂₋₆alkynylene group, and

R³′ represents a nitrogen-containing heterocyclic group optionallyhaving one or more substituents, a C₁₋₆ alkoxy group optionally havingone or more substituents, a mono- or di(C₁₋₆ alkyl)amino groupoptionally having one or more substituents, a mono- or di(C₂₋₆alkenyl)amino group optionally having one or more substituents, or acarbamoyl group optionally having one or more substituents), and

R¹′ and R²′ may form a ring together with the benzene ring).

[12] A tau aggregation inhibitor comprising the compound according toany one of the above [1] to [11] or a salt thereof as an activeingredient.

[13] A β-secretase inhibitor comprising the compound according to anyone of the above [1] to [11] or a salt thereof as an active ingredient.

[14] An Aβ aggregation inhibitor comprising the compound according toany one of the above [1] to [11] or a salt thereof as an activeingredient.

[15] A pharmaceutical composition comprising the compound according toany one of the above [1] to [11] or a salt thereof as an activeingredient.

[16] The pharmaceutical composition according to the above [15] for usein the prevention or treatment of a disease in which tau, β-secretase orAβ is involved.

[17] Use of the compound according to the above [1] or a salt thereof inthe production of a prophylactic or therapeutic preparation for adisease in which tau, β-secretase or Aβ is involved.

[18] The compound according to any one of the above [1] to [11] or asalt thereof for use in the prevention or treatment of a disease inwhich tau, β-secretase or Aβ is involved.

[19] A method for preventing or treating a disease in which tau,β-secretase or Aβ is involved, the method comprising the step ofadministering the compound according to the above [1] to a patient.

[20] The pharmaceutical composition according to the above [15] for usein the prevention or treatment of Alzheimer's disease.

[21] Use of the compound according to the above [1] or a salt thereof inthe production of a prophylactic or therapeutic preparation forAlzheimer's disease.

[22] The compound according to any one of the above [1] to [11] or asalt thereof for use in the prevention or treatment of Alzheimer'sdisease.

[23] A method for preventing or treating Alzheimer's disease, the methodcomprising the step of administering the compound according to the above[1] to a patient.

[24] An oral or parenteral preparation comprising the compound accordingto any one of the above [1] to [11] or a salt thereof and one or morepharmacologically acceptable carriers.

Advantageous Effects of Invention

The compound of the present invention is remarkably excellent in a tauaggregation inhibitory activity, a β-secretase inhibitory activity, anAβ aggregation inhibitory activity, and/or the like, and is thus usefulas a therapeutic drug for Alzheimer's disease and the like. The compoundof the present invention also has a high brain penetration, and thus ahighly efficient therapeutic drug can be provided.

DESCRIPTION OF EMBODIMENTS

The present invention will be described in detail below.

In the present invention, the term “halogen atom” means a fluorine atom,a chlorine atom, a bromine atom, and an iodine atom. The term “C₁₋₆alkyl group” means a linear or branched alkyl group of 1 to 6 carbonatoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, andn-hexyl groups. The term “halo C₁₋₆ alkyl group” means a linear orbranched 1- to 6-carbon alkyl group substituted with one or more halogenatoms that may be the same or different, and examples thereof includetrifluoromethyl, difluoromethyl, perfluoroethyl, hexafluoroisopropyl,perfluoroisopropyl, chloromethyl, bromomethyl, 1-bromoethyl, and2,3-dibromopropyl groups.

The term “C₁₋₆ alkoxy group” means a linear or branched alkoxy group of1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy,isopentyloxy, neopentyloxy, and n-hexyloxy groups. The term “halo C₁₋₆alkoxy group” means a linear or branched 1- to 6-carbon alkoxy groupsubstituted with one or more halogen atoms that may be the same ordifferent, and examples thereof include trifluoromethoxy,difluoromethoxy, perfluoroethoxy, perfluoroisopropoxy, chloromethoxy,bromomethoxy, 1-bromoethoxy, and 2,3-dibromopropoxy groups.

The term “C₁₋₆ acyl group” means a linear or branched acyl group of 1 to6 carbon atoms, and examples thereof include formyl, acetyl, propionyl,butyryl, 2-methylpropionyl, pivaloyl, pentanoyl, 3-methylbutyryl, andhexanoyl groups. The term “halo C₁₋₆ acyl group” means a linear orbranched 1- to 6-carbon acyl group substituted with one or more halogenatoms that may be the same or different, and examples thereof includechloroformyl, bromoformyl, dichloroacetyl, dibromoacetyl, andtrifluoroacetyl groups.

The term “C₁₋₆ alkylsulfonyl group” means a linear or branchedalkylsulfonyl group of 1 to 6 carbon atoms, and examples thereof includemethylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,n-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,n-pentylsulfonyl, isopentylsulfonyl, and n-hexylsulfonyl groups. Theterm “halo C₁₋₆ alkylsulfonyl group” means a linear or branched 1- to6-carbon alkylsulfonyl group substituted with one or more halogen atomsthat may be the same or different, and examples thereof includetrifluoromethylsulfonyl, difluoromethylsulfonyl, perfluoroethylsulfonyl,perfluoroisopropylsulfonyl, chloromethylsulfonyl, bromomethylsulfonyl,1-bromoethylsulfonyl, and 2,3-dibromopropylsulfonyl groups.

The term “mono- or di(C₁₋₆ alkyl)amino group” means an amino group mono-or di-substituted with the above C₁₋₆ alkyl group, and examples thereofinclude methylamino, ethylamino, propylamino, isopropylamino,butylamino, sec-butylamino, tert-butylamino, dimethylamino,diethylamino, ethylmethylamino, dipropylamino, methylpropylamino, anddiisopropylamino groups. The term “C₁₋₆ alkylthio group” means a linearor branched alkylthio group of 1 to 6 carbon atoms, and examples thereofinclude methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, andn-hexylthio groups. The term “C₁₋₆ acylamino group” means an amino groupsubstituted with the above C₁₋₆ acyl group, and examples thereof includeacetylamino and propionylamino groups.

The term “C₂₋₆ alkenyl group” means a linear or branched alkenyl groupof 2 to 6 carbon atoms, and examples thereof include vinyl, propenyl,and butenyl groups. The term “C₂₋₆ alkenyloxy group” means a linear orbranched alkenyloxy group of 2 to 6 carbon atoms, and examples thereofinclude propenyloxy, butenyloxy, and pentenyloxy groups. The term “mono-or di(C₂₋₆ alkenyl)amino group” means an alkenyl amino group mono- ordi-substituted with the above C₂₋₆ alkenyl group, and examples thereofinclude vinylamino, propenylamino, butenylamino, and divinylaminogroups.

The term “C₂₋₆ alkenylthio group” means a linear or branched alkenylthiogroup of 2 to 6 carbon atoms, and examples thereof include vinylthio,1-propenylthio, isopropenylthio, 1-butenylthio, 2-butenylthio, and2-methylallylthio groups. The term “nitrogen-containing heterocyclicgroup” means a saturated or unsaturated heterocyclic group containingone or more nitrogen atoms and optionally containing one or more oxygenand/or sulfur atoms, and examples thereof include pyridyl, pyrimidyl,pyrazyl, morpholino, 4-(substituted)piperazino (e.g., 4-methylpiperazinoetc.), 1,1-dioxo-1,4-thiazinan-4-yl, piperidino, pyrrolidino, thiazolyl,azepan-1-yl, and 4-(substituted)-1,4-diazepano (e.g.,4-methyl-1,4-diazepano) groups.

The present invention relates to a compound represented by the followinggeneral formula (I):

anda salt thereof.

In the above general formula (I), R¹ represents a hydrogen atom, ahalogen atom, a hydroxy group, a nitro group, an amino group, a cyanogroup, a C₁₋₆ alkyl group optionally having one or more substituents, aC₁₋₆ alkoxy group optionally having one or more substituents, a mono- ordi(C₁₋₆ alkyl)amino group optionally having one or more substituents, aC₁₋₆ alkylthio group optionally having one or more substituents, a C₁₋₆alkylsulfonyl group optionally having one or more substituents, a C₁₋₆acyl group optionally having one or more substituents, a C₁₋₆ acylaminogroup optionally having one or more substituents, a C₂₋₆ alkenyl groupoptionally having one or more substituents, a C₂₋₆ alkenyloxy groupoptionally having one or more substituents, a mono- or di(C₂₋₆alkenyl)amino group optionally having one or more substituents, a C₂₋₆alkenylthio group optionally having one or more substituents, acarbamoyl group optionally having one or more substituents, or the like.

The substituents in R¹ are not particularly limited as long as theeffects of the present invention are not impaired, and examples thereofinclude a halogen atom, a hydroxy group, a nitro group, an amino group,a morpholino group, and a pyridyl group. R¹ is preferably a hydroxygroup, a C₁₋₆ alkyl group optionally having one or more substituents, aC₁₋₆ alkoxy group optionally having one or more substituents, or thelike, and is more preferably hydroxy, methoxy, ethoxy,morpholinomethoxy, morpholinoethoxy, pyridylmethoxy, or pyridylethoxygroup, or the like. The position of R¹ on the benzene ring is notparticularly limited as long as the effects of the present invention arenot impaired, but when the position of the carbon atom bound to thepyrazole ring via the vinyl group is assigned position 1, the positionof R¹ on the benzene ring is preferably position 2 or 3, more preferablyposition 2.

In the above general formula (I), R² represents a group represented bythe following general formula (II):

In the above general formula (II), m and n each represent an integer of0 or 1. A represents —O—, —NH—, —S—, —SO—, —SO₂—, or the like, andpreferably represents —O—, —SO₂—, or the like. Y represents a C₁₋₆alkylene group, a C₂₋₆ alkenylene group, a C₂₋₆ alkynylene group, or thelike, and preferably represents a methylene group, an ethylene group, orthe like. R³ represents a nitrogen-containing heterocyclic groupoptionally having one or more substituents, a C₁₋₆ alkoxy groupoptionally having one or more substituents, a mono- or di(C₁₋₆alkyl)amino group optionally having one or more substituents, a mono- ordi(C₂₋₆ alkenyl)amino group optionally having one or more substituents,or a carbamoyl group optionally having one or more substituents.

The substituents in R³ in the above general formula (II) are notparticularly limited as long as the effects of the present invention arenot impaired. In cases where R³ is a nitrogen-containing heterocyclicgroup, the substituents are preferably a halogen atom, a hydroxy group,a nitro group, an amino group, a C₁₋₆ alkyl group, a halo C₁₋₆ alkylgroup, a C₁₋₆ alkoxy group, a halo C₁₋₆ alkoxy group, a C₁₋₆ acyl group,a halo C₁₋₆ acyl group, a C₁₋₆ alkylsulfonyl group, a halo C₁₋₆alkylsulfonyl group, or the like. In cases where R³ is a C₁₋₆ alkoxygroup, the substituents are preferably a methoxy group, an ethoxy group,a 2-methoxyethoxy group, or the like. In cases where R³ is a mono- ordi(C₁₋₆ alkyl)amino group or a mono- or di(alkenyl)amino group, thesubstituents are preferably a C₁₋₆ alkoxy group, a halo C₁₋₆ alkoxygroup, a C₁₋₆ alkylsulfonyl group, a halo C₁₋₆ alkylsulfonyl group, orthe like. In cases where R³ is a carbamoyl group, the substituents arepreferably a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, or the like.

Preferred specific examples of the group represented by R³ includepyridyl, pyrimidyl, pyrazyl, morpholino, 4-(substituted)piperazino(e.g., 4-methylpiperazino), 4-(substituted)-1,4-diazepano (e.g.,4-methyl-1,4-diazepano), 1,1-dioxo-1,4-thiazinan-4-yl, piperidino,pyrrolidino, thiazolyl, methoxy, ethoxy, propoxy, dimethylamino,diethylamino, isopropylamino, N,N-bis(2-methoxyethyl)amino,N-2-methoxyethyl-N-methylamino, N,N-bis(2-methylsulfonylethyl)amino,N-methyl-N-(2-methylsulfonylethyl)amino, and dimethylcarbamoyl groups.

Particularly preferred specific examples of the group represented by R²include morpholinoethoxy, morpholinomethoxy, pyridylmethoxy,pyridylethoxy, 2-pyrrolidinoethoxy, 2-piperidinoethoxy,2-(4-(substituted)piperazino)ethoxy,2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy, morpholinomethyl,(4-(substituted)piperazino)methyl, (1,1-dioxo-1,4-thiazinan-4-yl)methyl,piperidinomethyl, pyrrolidinomethyl, 2-morpholinoethyl,2-(4-(substituted)piperazino)ethyl,2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl, 2-piperidinoethyl,2-pyrrolidinoethyl, 2-morpholinoethanesulfonyl, methoxymethoxy,methoxyethoxy, methoxymethyl, methoxyethyl, dimethylamino, diethylamino,isopropylamino, N,N-bis(2-methoxyethyl)amino,N-2-methoxyethyl-N-methylamino, N,N-bis(2-methylsulfonylethyl)amino,N-methyl-N-(2-methylsulfonylethyl)amino, dimethylaminomethyl,diethylaminomethyl, N,N-bis(2-methoxyethyl)aminomethyl,dimethylaminoethoxy, 4-(substituted)piperazino,4-(substituted)-1,4-diazepano, and dimethylcarbamoylethoxy groups. Thesubstituents represented by the term “substituted” enclosed in theparentheses are not particularly limited as long as the presentinvention is not impaired, but are preferably a hydrogen atom, a C₁₋₆alkyl group, or the like, and are particularly preferably a hydrogenatom, a methyl group, an ethyl group, an isopropyl group, or the like.The position of R² on the benzene ring is not particularly limited aslong as the effects of the present invention are not impaired, but whenthe position of the carbon atom bound to the pyrazole ring via the vinylgroup is assigned position 1, the position of R² on the benzene ring ispreferably position 3 or 4, more preferably position 4.

In the above general formula (I), R¹ and R² may be joined together toform a ring. In this case, R¹ and R² form a fused ring or the liketogether with the benzene ring to which R¹ and R² are attached. Examplesof the fused ring include a 1,3-benzodioxole group optionally having oneor more substituents, a 1,4-benzodioxan-5-yl group optionally having oneor more substituents, a 1,4-benzodioxan-6-yl group optionally having oneor more substituents, a 1,4-benzodioxin-6-yl group optionally having oneor more substituents, a 1,4-benzodioxin-2-yl group optionally having oneor more substituents, a quinolino group optionally having one or moresubstituents, an isoquinolino group optionally having one or moresubstituents, a quinoxalino group optionally having one or moresubstituents, and an indolyl group optionally having one or moresubstituents.

The substituents in the above fused rings are not particularly limitedand examples thereof include those exemplified above for R¹, R² and R³.

In the above general formula (I), Ar represents a homocyclic orheterocyclic group optionally having one or more substituents. Thesubstituents are not particularly limited as long as the effects of thepresent invention are not impaired. Preferred examples thereof include ahalogen atom, a hydroxy group, a nitro group, an amino group, a C₁₋₆alkyl group, a halo C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a halo C₁₋₆alkoxy group, a C₁₋₆ acyl group, a halo C₁₋₆ acyl group, a C₁₋₆alkylsulfonyl group, and a halo C₁₋₆ alkylsulfonyl group, andparticularly preferred examples thereof include amino, hydroxy, methyl,ethyl, methoxy, and ethoxy groups. Preferred examples of the homocyclicor heterocyclic group include a monocyclic group such as phenyl,pyrrolyl, imidazolyl, furyl, pyridyl, and pyrazyl groups, and a bicyclicgroup having a benzene skeleton.

Preferred examples of the bicyclic group having a benzene skeletoninclude 1,3-benzodioxole, 1,4-benzodioxan-5-yl, 1,4-benzodioxan-6-yl,1,4-benzodioxin-6-yl, 1,4-benzodioxin-2-yl, quinolino, isoquinolino,quinoxalino, and indolyl groups. Particularly preferred examples of theindolyl group optionally having one or more substituents include a1-methylindolyl group.

In cases where Ar is a phenyl group optionally having one or moresubstituents, Ar is preferably a substituent represented by, forexample, the following general formula (III):

In the above general formula (I), R¹′ represents a hydrogen atom, ahalogen atom, a hydroxy group, a nitro group, an amino group, a cyanogroup, a C₁₋₆ alkyl group optionally having one or more substituents, aC₁₋₆ alkoxy group optionally having one or more substituents, a mono- ordi(C₁₋₆ alkyl)amino group optionally having one or more substituents, aC₁₋₆ alkylthio group optionally having one or more substituents, a C₁₋₆alkylsulfonyl group optionally having one or more substituents, a C₁₋₆acyl group optionally having one or more substituents, a C₁₋₆ acylaminogroup optionally having one or more substituents, a C₂₋₆ alkenyl groupoptionally having one or more substituents, a C₂₋₆ alkenyloxy groupoptionally having one or more substituents, a mono- or di(C₂₋₆alkenyl)amino group optionally having one or more substituents, a C₂₋₆alkenylthio group optionally having one or more substituents, acarbamoyl group optionally having one or more substituents, or the like.

The substituents in R¹′ are not particularly limited as long as theeffects of the present invention are not impaired, and examples thereofinclude a halogen atom, a hydroxy group, a nitro group, an amino group,a morpholino group, and a pyridyl group. R¹′ is preferably a hydroxygroup, a C₁₋₆ alkyl group optionally having one or more substituents, aC₁₋₆ alkoxy group optionally having one or more substituents, or thelike, and is more preferably hydroxy, methoxy, ethoxy,morpholinomethoxy, morpholinoethoxy, pyridylmethoxy, or pyridylethoxygroup, or the like. The position of R¹′ on the benzene ring is notparticularly limited as long as the effects of the present invention arenot impaired, but when the position of the carbon atom bound to thepyrazole ring via the vinyl group is assigned position 1, the positionof R¹′ on the benzene ring is preferably position 2 or 3, morepreferably position 2.

In the above general formula (III), R²′ represents a group representedby the following general formula (IV):

In the above general formula (IV), m′ and n′ each represent an integerof 0 or 1. A′ represents —O—, —NH—, —S—, —SO—, —SO₂—, or the like, andpreferably represents —O—, —SO₂—, or the like. Y′ represents a C₁₋₆alkylene group, a C₂₋₆ alkenylene group, a C₂₋₆ alkynylene group, or thelike, and preferably represents a methylene group, an ethylene group, orthe like. R³′ represents a nitrogen-containing heterocyclic groupoptionally having one or more substituents, a C₁₋₆ alkoxy groupoptionally having one or more substituents, a mono- or di(C₁₋₆alkyl)amino group optionally having one or more substituents, a mono- ordi(C₂₋₆ alkenyl)amino group optionally having one or more substituents,or a carbamoyl group optionally having one or more substituents.

The substituents in R³′ in the above general formula (IV) are notparticularly limited as long as the effects of the present invention arenot impaired. In cases where R³′ is a nitrogen-containing heterocyclicgroup, the substituents are preferably a halogen atom, a hydroxy group,a nitro group, an amino group, a C₁₋₆ alkyl group, a halo C₁₋₆ alkylgroup, a C₁₋₆ alkoxy group, a halo C₁₋₆ alkoxy group, a C₁₋₆ acyl group,a halo C₁₋₆ acyl group, a C₁₋₆ alkylsulfonyl group, a halo C₁₋₆alkylsulfonyl group, or the like. In cases where R³′ is a C₁₋₆ alkoxygroup, the substituents are preferably a methoxy group, an ethoxy group,a 2-methoxyethoxy group, or the like. In cases where R³′ is a mono- ordi(C₁₋₆ alkyl)amino group or a mono- or di(alkenyl)amino group, thesubstituents are preferably a C₁₋₆ alkoxy group, a halo C₁₋₆ alkoxygroup, a C₁₋₆ alkylsulfonyl group, a halo C₁₋₆ alkylsulfonyl group, orthe like. In cases where R³′ is a carbamoyl group, the substituents arepreferably a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, or the like.

Preferred specific examples of the group represented by R³′ includepyridyl, pyrimidyl, pyrazyl, morpholino, 4-(substituted)piperazino(e.g., 4-methylpiperazino), 1,1-dioxo-1,4-thiazinan-4-yl, piperidino,pyrrolidino, thiazolyl, methoxy, ethoxy, propoxy, dimethylamino,diethylamino, isopropylamino, N,N-bis(2-methoxyethyl)amino,N-2-methoxyethyl-N-methylamino, N,N-bis(2-methylsulfonylethyl)amino,N-methyl-N-(2-methylsulfonylethyl)amino, and dimethylcarbamoyl groups.

Particularly preferred specific examples of the group represented by R²′include morpholinoethoxy, morpholinomethoxy, pyridylmethoxy,pyridylethoxy, 2-pyrrolidinoethoxy, 2-piperidinoethoxy,2-(4-(substituted)piperazino)ethoxy,2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy, morpholinomethyl,(4-(substituted)piperazino)methyl, (1,1-dioxo-1,4-thiazinan-4-yl)methyl,piperidinomethyl, pyrrolidinomethyl, 2-morpholinoethyl,2-(4-(substituted)piperazino)ethyl,2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl, 2-piperidinoethyl,2-pyrrolidinoethyl, 2-morpholinoethanesulfonyl, methoxymethoxy,methoxyethoxy, methoxymethyl, methoxyethyl, dimethylamino, diethylamino,isopropylamino, N,N-bis(2-methoxyethyl)amino,N-2-methoxyethyl-N-methylamino, N,N-bis(2-methylsulfonylethyl)amino,N-methyl-N-(2-methylsulfonylethyl)amino, dimethylaminomethyl,diethylaminomethyl, N,N-bis(2-methoxyethyl)aminomethyl,dimethylaminoethoxy, and dimethylcarbamoylethoxy groups. Thesubstituents represented by the term “substituted” enclosed in theparentheses are not particularly limited as long as the presentinvention is not impaired, but are preferably a hydrogen atom, a C₁₋₆alkyl group, or the like, and are particularly preferably a hydrogenatom, a methyl group, an ethyl group, an isopropyl group, or the like.The position of R²′ on the benzene ring is not particularly limited aslong as the effects of the present invention are not impaired, but whenthe position of the carbon atom bound to the pyrazole ring via the vinylgroup is assigned position 1, the position of R²′ on the benzene ring ispreferably position 3 or 4, more preferably position 4.

In the above general formula (III), R¹′ and R²′ may be joined togetherto form a ring. In this case, R¹′ and R²′ form a fused ring or the liketogether with the benzene ring to which R¹′ and R²′ are attached.Examples of the fused ring include those exemplified above for thebicyclic group having a benzene skeleton.

The substituent represented by the general formula (III) may be the sameas or different from the phenyl group substituted with R¹ and R² in thegeneral formula (I). When they are the same, the compound or a saltthereof is easier to synthesize and is thus industrially preferable.

In the general formula (I), in cases where R² is a morpholinomethoxy,morpholinoethoxy or pyridylmethoxy group, Ar is particularly preferably,for example, a phenyl group optionally having one or more substituents(e.g., a morpholinomethoxy phenyl group, a dimethylcarbamoylmethoxyphenyl group, a dimethoxyphenyl group, or the like), a pyrrolyl groupoptionally having one or more substituents, or a bicyclic group having abenzene skeleton and optionally having one or more substituents (e.g., a1,3-benzodioxole group, a 1,4-benzodioxan-6-yl group, an indolyl group,a 1-methylindolyl group, or the like). In cases where R² is apyridylmethoxy group, Ar is particularly preferably, for example, apyrrolyl group optionally having one or more substituents, or a bicyclicgroup having a benzene skeleton (e.g., a 1-methylindolyl group or thelike). Preferably, R¹, R² and/or Ar are basic groups so that thecompound or a salt thereof is excellent in water solubility andtherefore can readily undergo oral absorption and the like.

A salt of the compound represented by the general formula (I) is alsoencompassed in the present invention. The salt is preferably apharmacologically acceptable salt and examples thereof includehydrohalic acid salts such as hydrofluoride, hydrochloride,hydrobromide, and hydroiodide; inorganic acid salts such as sulfate,nitrate, perchlorate, phosphate, carbonate, and bicarbonate; organiccarboxylic acid salts such as acetate, oxalate, maleate, tartrate, andfumarate; organic sulfonic acid salts such as methanesulfonate,trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, and camphorsulfonate; amino acid salts such asaspartate and glutamate; amine salts such as trimethylamine salt,triethylamine salt, procaine salt, pyridine salt, andphenethylbenzylamine salt; alkali metal salts such as sodium salt andpotassium salt; alkaline earth metal salts such as magnesium salt andcalcium salt; etc. In view of the water solubility, oral absorbability,efficacy, and the like, preferred are hydrochloride and oxalate.

The compound represented by the general formula (I) can be produced byknown methods described in, for example, Rajeshwar Narlawar et al., ChemMed Chem 2008, 3, 165-172, WO 2008/066151, WO 2009/145219, or the like,or by any combination of the methods described in the literature, or bya method known per se or an equivalent method thereto. Specifically, thecompound can be produced by, for example, the following Steps 1 and 2,but the production method is not limited thereto.

Ar¹ in the above formula is either the phenyl ring substituted with R¹and R² or a ring represented by Ar in the compound represented by thegeneral formula (I) of the present invention, and Ar² is the other one.In Step 1, an aldehyde represented by the general formula (A) is allowedto react with a compound represented by the general formula (B) in thepresence of a solvent and a catalyst to give a diketone represented bythe general formula (C).

The solvent used in the reaction is not particularly limited as long asit does not inhibit the reaction, and examples thereof include ethylacetate, N,N-dimethylacetamide, N,N-dimethylformamide,1-methyl-2-pyrrolidone, dimethylsulfoxide, tetrahydrofuran,acetonitrile, etc. These solvents may be used alone or in combination oftwo or more kinds thereof at a given mixing ratio.

The catalyst used in the reaction is also not particularly limited.Examples thereof include bases such as a primary amine and a secondaryamine, and specific examples thereof include n-butylamine, ethanolamine,piperidine, morpholine, etc.

In Step 1, a water scavenger may be added in order to capture the waterproduced by the reaction. Examples of the water scavenger include analkyl borate, an alkyl phosphate, an orthoester, etc., and specificexamples thereof include trimethyl orthoformate and tri-n-butyl borate.

In Step 1, the quantitative ratio of the aldehyde represented by thegeneral formula (A) and the compound represented by the general formula(B) is not particularly limited as long as the reaction proceeds.However, in view of the reaction efficiency and the like, the amount ofthe compound is preferably 0.5 to 10 mol, more preferably 0.5 to 2 mol,relative to 1 mol of the aldehyde.

In Step 1, the reaction temperature is not particularly limited as longas the reaction proceeds. However, in view of the reaction efficiencyand the like, the reaction temperature is preferably 0 to 200° C., morepreferably 50 to 100° C.

In Step 1, the reaction duration is not particularly limited as long asthe reaction proceeds. However, in view of the production efficiency andthe like, the reaction duration is preferably 0.5 to 48 hours, morepreferably 1 to 24 hours.

The aldehyde represented by the general formula (A) and the compoundrepresented by the general formula (B) that are used in Step 1 may becommercially available products or those synthesized by a known method(for example, the method described in WO 2008/066151 or WO 2009/145219)or other methods.

In Step 2, a diketone represented by the general formula (C) is allowedto react with a hydrazine in the presence of a solvent to give acompound represented by the general formula (I).

The hydrazine used in the reaction is not particularly limited andexamples thereof include hydrazine monohydrate, hydrazine aqueoussolution, anhydrous hydrazine, hydrazine acetate, hydrazinemonohydrochloride, hydrazine dihydrochloride, a derivative thereof, etc.

The solvent used in the reaction is not particularly limited as long asit does not inhibit the reaction and examples thereof include proticsolvents such as acetic acid, methanol, ethanol, and water; non-proticsolvents such as ethyl acetate, toluene, tetrahydrofuran, methylenechloride, chloroform, etc. These solvents may be used alone or, ifdesired, in combination of two or more kinds thereof at a given mixingratio.

In Step 2, the quantitative ratio of the diketone represented by thegeneral formula (C) and the hydrazine is not particularly limited aslong as the reaction proceeds. However, in view of the reactionefficiency and the like, the amount of the hydrazine is preferably 1 to50 mol, more preferably 2 to 10 mol, relative to 1 mol of the diketone.

In Step 2, the reaction temperature is not particularly limited as longas the reaction proceeds. However, in view of the reaction efficiencyand the like, the reaction temperature is preferably 20 to 120° C., morepreferably 50 to 80° C.

In Step 2, the reaction duration is not particularly limited as long asthe reaction proceeds. However, in view of the production efficiency andthe like, the reaction duration is preferably 0.2 to 24 hours, morepreferably 0.5 to 6 hours.

The compound of the present invention may be administered to a subject,alone or in combination with one or more of other compounds of thepresent invention, or with one or more compounds other than thecompounds of the present invention. The compound of the presentinvention may be administered as a preparation or pharmaceuticalcomposition comprising one or more pharmacologically acceptablecarriers. The effective dosage of the compound of the present inventionas an active ingredient and frequency of administration may vary withthe dosage form, the age, body weight, symptoms, etc. of the patient,and the like, but the daily dosage is usually about 0.01 to 100 mg/kg,more preferably about 1 to 50 mg/kg.

The subject is not particularly limited and examples thereof includemammals such as a human, a monkey, a hamadryas baboon, a chimpanzee, amouse, a rat, a guinea pig, a hamster, a rabbit, a cat, a dog, a sheep,a goat, a pig and a cattle.

The route of administration of the preparation or pharmaceuticalcomposition comprising the compound of the present invention as anactive ingredient is not particularly limited, and the preparation orpharmaceutical composition may be administered orally or parenterally bya usual method. Examples of the parenteral administration include rectaladministration, nasal administration, transpulmonary administration,dermal administration, and injection administration (e.g., intravenousadministration, intraspinal administration, epidural administration,intramuscular administration, subcutaneous administration,intraperitoneal administration, intraarterial administration,intraarticular administration, intracardiac administration, intracysticadministration, intracutaneous administration, intralesionaladministration, intraocular administration, intrathoracicadministration, subarachnoid administration, intrauterineadministration, intraventricular administration, etc.).

The form of the preparation or pharmaceutical composition comprising thecompound of the present invention as an active ingredient is notparticularly limited, and examples thereof include oral or parenteralpreparations such as tablets, powders, granules, capsules, oralsolutions, emulsions, elixirs, lemonades, suspensions, syrups,oromucosal tablets, oral jellies, inhalations, suppositories,injections, ointments, ophthalmic ointments, ophthalmic preparations,nasal preparations, ear preparations, patches, solutions for externalapplication.

The dosage of the preparation or pharmaceutical composition of thepresent invention can be determined as appropriate depending on theseverity of the symptom, the age, sex, and body weight of the patient,the route of administration, the type of the salt, the specific disease,etc.

Since the compound of the present invention has a tau aggregationinhibitory activity, a β-secretase inhibitory activity, and/or an Aβaggregation inhibitory activity, the compound of the present inventionis effective in preventing and treating diseases in which tau,β-secretase or Aβ is involved, such as Alzheimer's disease (familialAlzheimer's disease and sporadic Alzheimer's disease), senile dementia,Down syndrome, Parkinson's disease, Creutzfeldt-Jakob disease,amyotrophic lateral sclerosis, diabetic neuropathy, Huntington's chorea,multiple sclerosis, etc. Among these nervous diseases, the compound ofthe present invention is especially effective in preventing and treatingAlzheimer's disease.

The compound of the present invention can be formulated by a commonlyused method into dosage forms such as tablets, powders, granules,capsules, oral solutions, emulsions, elixirs, lemonades, suspensions,syrups, oromucosal tablets, oral jellies, inhalations, suppositories,injections, ointments, ophthalmic ointments, ophthalmic preparations,nasal preparations, ear preparations, patches, solutions for externalapplication, etc. For the formulation into such dosage forms,excipients, binders, lubricants, colorants and flavor modifiers that areusually used for the formulation of medicines can be used, and as neededstabilizers, emulsifiers, absorption enhancers, surfactants, pHadjusters, preservatives, antioxidants, and/or the like can also beused. Thus, ingredients that are usually used as raw materials of apharmaceutical preparation may be mixed with the compound and formulatedinto a dosage form by a conventional method.

For example, in the production of oral preparations, a crystalline oramorphous compound of the present invention is mixed with excipients,and as needed with additives such as binders, disintegrators,lubricants, colorants, flavor modifiers, etc., and formed into powders,fine granules, granules, tablets, coated tablets, capsules, etc. by aconventional method. Examples of the additives include animal andvegetable fats and oils such as soybean oil, beef tallow, and syntheticglyceride; hydrocarbons such as liquid paraffin, squalane, and hardparaffin; ester oils such as octyldodecyl myristate and isopropylmyristate; higher alcohols such as cetostearyl alcohol and behenylalcohol; silicone resins; silicone oils; surfactants such aspolyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerinfatty acid ester, polyoxyethylene sorbitan fatty acid ester,polyoxyethylene hardened castor oil, andpolyoxyethylene-polyoxypropylene block copolymer; water soluble polymerssuch as hydroxyethyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, polyacrylate, carboxy vinylpolymer, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose;lower alcohols such as ethanol and isopropanol; polyalcohols such asglycerin, propylene glycol, dipropylene glycol, and sorbitol; sugarssuch as glucose and sucrose; inorganic powders such as anhydrous silicicacid, magnesium aluminum silicate, and aluminium silicate; purifiedwater; etc.

Examples of the excipients include lactose, corn starch, saccharose,glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide,etc. Examples of the binders include polyvinyl alcohol, polyvinyl ether,methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin,shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose,polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene blockpolymer, meglumine, etc. Examples of the disintegrators include starch,agar, gelatin powder, crystalline cellulose, calcium carbonate, sodiumbicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulosecalcium, etc. Examples of the lubricants include magnesium stearate,talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc.Examples of the colorants include a colorant that is approved asadditives to a medicine, etc. Examples of the flavor modifiers includecocoa powder, menthol, aromatic powder, mentha oil, borneol, cinnamonpowder, etc.

Needless to say, in the production of the tablets or granules, coatingof the tablets or granules with a sugar or the like may be performed asneeded. In the production of solutions such as syrups, emulsions,elixirs, lemonades, suspensions, and injections, the compound of thepresent invention can be mixed as needed with further additives such aspH adjusters, solubilizers, emulsifiers, disintegrators, isotonicagents, solubilization assisting agents, stabilizers, and the like, andformed into such solutions by a conventional method.

In the production of external medicines, the production method is notlimited and the production can be carried out by a conventional method.That is, for the formulation of external medicines, various types of rawmaterials that are usually used for medicines, quasi drugs, cosmetics,or the like can be used as a base ingredient. Specific examples of thebase ingredients to be used include animal and vegetable oils, mineraloils, ester oils, waxes, higher alcohols, fatty acids, silicone oils,surfactants, phospholipids, alcohols, polyalcohols, water solublepolymers, clay minerals, water-insoluble natural or synthetic polymerssuch as resins, plastics and rubbers, purified water, etc. Further, pHadjusters, antioxidants, chelating agents, antibacterial and antifungalagents, colorants, flavors, and/or the like can be added as needed. Thebase ingredients of the external medicines of the present invention arenot limited to the above ingredients. As needed, other ingredients canbe added and examples thereof include ingredients having adifferentiation inducing activity, blood flow increasing agents,bactericides, anti-inflammatories, cell activators, vitamins, aminoacids, moisturizers, keratolytic agents, etc. The amount of the baseingredients to be added is determined so that the concentration will bea usual base ingredient concentration in the production of externalmedicines.

The compound of the present invention may be provided as a food ordrink, a feed, or a food additive.

The food or drink of the present invention may contain one or more typesof food additives commonly used in food or drink, and examples of thefood additives include sweeteners, colorants, preservatives, thickeningstabilizers, antioxidants, color fixatives, bleaching agents, antifungalagents, gum bases, bittering agents, enzymes, brighteners, acidulants,seasonings, emulsifiers, fortifiers, processing aids, flavors, and spiceextracts. The food or drink of the present invention includes healthfoods, functional foods, foods for specified health use, foods forbabies, foods for small children, foods for pregnant women and nursingmothers, foods for elderly people, and foods for sick people.

The form of the food or drink of the present invention is notparticularly limited. Specific examples thereof include so-calleddietary supplements in forms of tablets, granules, powders, energydrinks, or the like. Other examples thereof include drinks, such as teadrink, refreshing drink, carbonated drink, nutritional drink, fruitjuice, and lactic drink; noodles, such as buckwheat noodle, wheatnoodle, Chinese noodle, and instant noodle; sweets and bakery products,such as drop, candy, gum, chocolate, snack, biscuit, jelly, jam, cream,pastry, and bread; fishery or livestock products, such as fish sausage,ham, and sausage; dairy products, such as processed milk and fermentedmilk; fats, oils and processed foods thereof, such as vegetable oil, oilfor deep frying, margarine, mayonnaise, shortening, whipped cream, anddressing; seasonings, such as sauce and dipping sauce; retort pouchfoods, such as curry, stew, rice-bowl cuisine, porridge, and rice soup;and frozen desserts, such as ice cream, sherbet, and shaved ice.

The amount of intake of the food or drink of the present invention isnot particularly limited, and may be determined depending on the form ofthe food or drink, the age, sex, condition, and the like of the subjectwho is to take the food or drink, and other conditions.

The compound of the present invention or a salt thereof can be used fora therapeutic method for a disease in which tau, β-secretase or Aβ isinvolved. Specific examples of the method include the following (a) to(c):

(a) a therapeutic method for a disease in which tau is involved, themethod comprising the step of administering a compound represented bythe general formula (I) or a salt thereof to a patient with a disease inwhich tau is involved;

(b) a therapeutic method for a disease in which β-secretase is involved,the method comprising the step of administering a compound representedby the general formula (I) or a salt thereof to a patient with a diseasein which β-secretase is involved; and

(c) a therapeutic method for a disease in which Aβ is involved, themethod comprising the step of administering a compound represented bythe general formula (I) or a salt thereof to a patient with a disease inwhich Aβ is involved. The diseases in which tau, β-secretase or Aβ isinvolved preferably include diseases of which the onset mechanisminvolves tau, β-secretase or Aβ. Specific examples of such diseasesinclude Alzheimer's disease (familial Alzheimer's disease and sporadicAlzheimer's disease), senile dementia, Down syndrome, Parkinson'sdisease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis,diabetic neuropathy, Huntington's chorea, multiple sclerosis, etc. Amongthese, preferred is Alzheimer's disease.

The route of administration, dosage form, and dosage of the compound ofthe present invention, and the subject to which the compound is to beadministered may be the same as those described above for thepreparation comprising the compound of the present invention.

The compound of the present invention can also be used for a method forinhibiting tau aggregation, a method for inhibiting β-secretase, and amethod for inhibiting Aβ aggregation. Specific examples of the methodinclude the following (d) to (i):

(d) a method for inhibiting tau aggregation, the method comprising thestep of administering a compound represented by the general formula (I)or a salt thereof to a mammal including human, thereby inhibiting tauaggregation in the body of the mammal including human;(e) a method for inhibiting tau aggregation, the method comprising thestep of bringing a compound represented by the general formula (I) or asalt thereof in contact with tau;(f) a method for inhibiting β-secretase, the method comprising the stepof administering a compound represented by the general formula (I) or asalt thereof to a mammal including human, thereby inhibiting β-secretasein the living human body;(g) a method for inhibiting β-secretase, the method comprising the stepof bringing a compound represented by the general formula (I) or a saltthereof in contact with β-secretase;(h) a method for inhibiting Aβ aggregation, the method comprising thestep of administering a compound represented by the general formula (I)or a salt thereof to a mammal including human, thereby inhibiting Aβaggregation in the body of the mammal including human; and(i) a method for inhibiting Aβ aggregation, the method comprising thestep of bringing a compound represented by the general formula (I) or asalt thereof in contact with Aβ.

The salt in the above methods may be a pharmacologically acceptablesalt.

The present invention also includes, as one embodiment, use of thecompound of the present invention or a salt thereof in the production ofa prophylactic or therapeutic preparation for a disease in which tau,β-secretase or Aβ is involved. The disease in which tau, β-secretase orAβ is involved may be the same as those described above, and ispreferably Alzheimer's disease.

The present invention also includes, as another embodiment, the compoundof the present invention or a salt thereof for use in the prevention ortreatment of a disease in which tau, β-secretase or Aβ is involved. Thedisease in which tau, β-secretase or Aβ is involved may be the same asthose described above, and is preferably Alzheimer's disease.

EXAMPLES

The present invention will be described in further detail with referenceto Examples etc., but the present invention is not limited thereto.Various modifications of the present invention can be made by a personwho has common knowledge in the art, without departing from the scope ofthe technical idea of the present invention.

In Examples, the compound of the general formula (I) is detected as amixture of two tautomers represented by the general formulas (I) and(I′) shown below, depending on the measurement conditions of ¹H-NMR. Thetwo tautomers are isomers of the same substance. Therefore, thesynthetic compounds in Examples can be named based on either the generalformula (I) or the general formula (I′).

A compound represented by the above general formula (C) is an importantintermediate in the present invention. The compound of the generalformula (C) can exist in tautomeric forms including a keto form and anenol form, and these tautomeric forms are the same substance. Therefore,such an intermediate can be named based on any of the general formula(C), the general formula (C′), and the general formula (C″).

The following abbreviations are also used herein.

TABLE 1 Abbreviation Reagent, solvent, etc. AcOEt Ethyl acetate AcOHAcetic acid CHCl₃ Chloroform IBCF Isobutyl chloroformate K₂CO₃ Potassiumcarbonate LAH Lithium aluminium hydride MgSO₄ Magnesium sulfate Na₂SO₄Sodium sulfate NaHCO₃ Sodium hydrogen carbonate NaOH Sodium hydroxidePTLC Preparative thin-layer chromatography THF Tetrahydrofuran

Example 1 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 1-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

To 2.5 g of (E)-6-(1H-indol-6-yl)hex-5-ene-2,4-dione were added 44 mL ofAcOEt and 1.07 g of boron oxide, and the mixture was stirred at 70° C.for 40 minutes. To this, 2.27 g of 4-(2-morpholinoethoxy)benzaldehydeand 7.07 mL of tributyl borate were successively added, and the mixturewas stirred at the same temperature for 40 minutes. Then, 0.11 mL ofpiperidine was added, and the mixture was stirred at 70° C. for 1.5hours and was allowed to cool back to room temperature. To the reactionmixture, 22 mL of a 20% K₂CO₃ aqueous solution and 20 mL of THF wereadded and the mixture was stirred at room temperature for 10 minutes.The organic layer was separated, washed with saturated brine, dried overMgSO₄, and concentrated. The residue was purified by silica gel columnchromatography (CHCl₃/acetone or CHCl₃/methanol system) to give 1.62 gof the title compound (33% yield).

Example 1-2 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

To 1.5 g of(1E,6E)-1-(1H-indol-6-yl)-7-[4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dionewere added 13.5 mL of AcOH and 1.31 mL of hydrazine monohydrate, and themixture was stirred at 60° C. for 3 hours. The reaction mixture wasallowed to cool back to room temperature and poured into a stirringmixture of 18.7 g of K₂CO₃, 95 mL of cold water, 30 mL of AcOEt and 20mL of THF. The organic layer was separated, washed with saturated brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography (CHCl₃/acetone or CHCl₃/methanol system) togive 0.62 g of the title compound (42% yield).

Example 2 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1,3-benzodioxol-5-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]ethyl]morpholineExample 2-1 Synthesis of(1E,6E)-1-(1,3-benzodioxol-5-yl)-7-[2-methoxy-4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 2-2 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1,3-benzodioxol-5-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 3 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1,3-benzodioxol-5-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 3-1 Synthesis of(1E,6E)-1-(1,3-benzodioxol-5-yl)-7-[4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 3-2 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1,3-benzodioxol-5-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 4 Synthesis of6-[(E)-2-[3-[(E)-2-[2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1H-indoleExample 4-1 Synthesis of2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]benzoic acid methyl ester

To 100 mL of ethanol were added 10.0 g of 1-methylpiperazine and 20.2 gof triethylamine. To the mixture cooled with ice, 25 mL of a solution of24.6 g of 4-(bromomethyl)-2-methoxy-benzoic acid methyl ester in ethanolwas added dropwise. The mixture was stirred at room temperature for 18hours. The reaction mixture was concentrated. To the residue, 75 mL ofwater and 250 mL of methylene chloride were added, and the organic layerwas separated. The obtained organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by amino-silica gel columnchromatography (heptane/AcOEt system) to give 22.4 g of the titlecompound (85% yield).

Example 4-2 Synthesis of[2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl]methanol

To 200 mL of a suspension of 5.21 g of LAH in THF cooled with ice wasadded dropwise, under argon flow, 50 mL of a solution of 25.5 g of2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]benzoic acid methyl ester inTHF. The mixture was stirred under ice cooling for 1 hour and furtherstirred at room temperature for 22 hours. To the reaction mixture cooledwith ice, 25 mL of a 10% NaOH water was added dropwise. After 30-minutestirring, the mixture was filtered through Celite. The filtrate waswashed with 150 mL of THF and then was concentrated. To the residue, 50mL of saturated brine and 300 mL of dichloromethane were added, and theorganic layer was separated. The organic layer was concentrated. Theresidue was purified by silica gel column chromatography (CHCl₃/methanolsystem) to give 22.4 g of the title compound (98% yield).

Example 4-3 Synthesis of2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]benzaldehyde

To 220 mL of a solution of 22.2 g of[2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl]methanol in CHCl₃was added 61.8 g of manganese dioxide, and the mixture was stirred at55° C. for 13 hours. The reaction mixture was allowed to stand to cool.After insoluble matter was filtered off, the mother liquor wasconcentrated to give 21.8 g of the title compound (99% yield).

Example 4-4 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl]hepta-1,6-diene-3,5-dione

To 200 mL of a solution of 7.56 g of(E)-6-(1H-indol-6-yl)hex-5-ene-2,4-dione in AcOEt was added 3.24 g ofboron oxide, and the mixture was stirred at 70° C. for 1 hour. To this,15 mL of a solution of 8.68 g of2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]benzaldehyde in AcOEt and18.3 mL of triisopropyl borate were successively added, and the mixturewas stirred at the same temperature for 40 minutes. Then, 10 mL of asolution of 0.35 mL of piperidine in AcOEt was added. The mixture wasstirred at 70° C. for 3 hours and was allowed to cool back to roomtemperature. To the reaction mixture, 100 mL of a 10% K₂CO₃ aqueoussolution was added, and the mixture was stirred for 1 hour. The organiclayer was separated and concentrated. The residue was purified byamino-silica gel column chromatography (heptane/AcOEt system) to give7.14 g of the title compound (47% yield).

Example 4-5 Synthesis of6-[(E)-2-[3-[(E)-2-[2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1H-indole

The title compound was obtained in the same manner as in Example 1-2.

Example 5 Synthesis of3,5-bis[(E)-2-[4-(2-morpholinoethoxy)phenyl]vinyl]-1H-pyrazole Example5-1 Synthesis of(1E,6E)-1,7-bis[4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

To 2.0 g of pentane-2,4-dione were added 10.0 mL of AcOEt and 0.70 g ofboron oxide, and the mixture was stirred at 70° C. for 1 hour. To thereaction mixture, 30 mL of a solution of 9.4 g of4-(2-morpholinoethoxy)benzaldehyde in AcOEt and 10.7 mL of tributylborate were successively added, and the mixture was stirred at the sametemperature for 1 hour. To this, 0.4 mL of 1-butylamine was added, andthe mixture was stirred at 70° C. for 2.5 hours and was allowed to coolback to room temperature. To the reaction mixture, 50 mL of a 10% K₂CO₃aqueous solution and 30 mL of THF were added, and the mixture wasstirred at room temperature for 10 minutes. The organic layer wasseparated, washed with saturated brine, dried over MgSO₄, andconcentrated. The residue was treated with 100 mL of diethyl ether togive 2.51 g of the title compound as a powder (24% yield).

Example 5-2 Synthesis of3,5-bis[(E)-2-[4-(2-morpholinoethoxy)phenyl]vinyl]-1H-pyrazole

The title compound was obtained in the same manner as in Example 1-2.

Example 6 Synthesis ofN,N-dimethyl-2-[4-[(E)-2-[3-[(E)-2-[4-(2-morpholinoethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]phenoxy]acetamideExample 6-1 Synthesis of(E)-6-[4-(2-morpholinoethoxy)phenyl]hex-5-ene-2,4-dione

To 30.0 g of (E)-3-[4-(2-morpholinoethoxy)phenyl]-2-propenoic acid wasadded 600 mL of THF under argon flow. To the mixture cooled with ice,12.1 g of triethylamine and 15.5 g of IBCF were successively addeddropwise. The mixture was stirred at room temperature for 2 hours toprepare an acid anhydride. In a separate container, 200 mL of THF and16.3 g of acetylacetone were added to 15.5 g of magnesium chloride underargon flow. To the mixture cooled with ice, 17.5 mL of pyridine wasadded dropwise over 25 minutes. The mixture was stirred at roomtemperature for 2 hours. To the reaction mixture cooled with ice, theabove-prepared acid anhydride cooled with ice was added dropwise over 45minutes. The mixture was stirred at room temperature overnight. Thereaction mixture was added to 2 L of a saturated aqueous ammoniumchloride solution and 2 L of CHCl₃, and the organic layer was separated.The obtained organic layer was dried over Na₂SO₄ and concentrated.

The residue was dissolved in 100 mL of THF. While the mixture wasstirred under ice cooling, 40 mL of a 28% ammonia water was addeddropwise. The mixture was stirred at the same temperature for 1 hour.The reaction mixture was added to 1 L of CHCl₃ and 1 L of saturatedbrine, and the organic layer was separated. The obtained organic layerwas dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel column chromatography (CHCl₃/methanol system) to give 26.5 gof the title compound (77% yield).

Example 6-2 Synthesis ofN,N-dimethyl-2-[4-[(1E,6E)-7-[4-(2-morpholinoethoxy)phenyl]-3,5-dioxo-hepta-1,6-dienyl]phenoxy]acetamide

The title compound was obtained in the same manner as in Example 4-4.

Example 6-3 Synthesis ofN,N-dimethyl-2-[4-[(E)-2-[3-[(E)-2-[4-(2-morpholinoethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]phenoxy]acetamide

To 2.70 g ofN,N-dimethyl-2-[4-[(1E,6E)-7-[4-(2-morpholinoethoxy)phenyl]-3,5-dioxo-hepta-1,6-dienyl]phenoxy]acetamidewere added 2.80 g of hydrazine dihydrochloride and 54 mL of methanol,and the mixture was stirred at 40° C. overnight. The reaction mixturewas allowed to stand to cool, and poured into 200 mL of a saturatedaqueous NaHCO₃ solution. To this, 600 mL of AcOEt was added, and theorganic layer was separated. The obtained organic layer was washed withsaturated brine, dried over Na₂SO₄, and concentrated. The residue waspurified by silica gel column chromatography (CHCl₃/methanol system) togive 1.76 g of the title compound (66% yield).

Example 7 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 7-1 Synthesis of(1E,6E)-1-(3,4-dimethoxyphenyl)-7-[4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 4-4.

Example 7-2 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 6-3.

Example 8 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(3H-benzimidazol-5-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 8-1 Synthesis of(1E,6E)-1-(3H-benzimidazol-5-yl)-7-[4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 4-4.

Example 8-2 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(3H-benzimidazol-5-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 6-3.

Example 9 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(1H-pyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 9-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1H-pyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 9-2 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(1H-pyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

To 30 mg of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1H-pyrrol-2-yl)hepta-1,6-diene-3,5-dionewere added 1 mL of THF, 3 μL of AcOH and 4 μL of hydrazine monohydrate,and the mixture was stirred at 60° C. for 4 hours. To this, 500 μL ofAcOH was added and the mixture was stirred at 80° C. for 1 hour. Tothis, 4 μL of hydrazine monohydrate was added and the mixture wasstirred at 80° C. for 1 hour. The reaction mixture was allowed to coolback to room temperature, and a saturated aqueous NaHCO₃ solution wasadded. After extraction with AcOEt, the organic layer was separated. Theobtained organic layer was washed with saturated brine, dried overMgSO₄, and concentrated. The residue was purified by PTLC(CHCl₃/methanol or AcOEt system) to give 8 mg of the title compound (27%yield).

Example 10 Synthesis of3-benzyloxy-N,N-diethyl-4-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]anilineExample 10-1 Synthesis of (E)-6-(1-methylindol-6-yl)hex-5-ene-2,4-dione

The title compound was obtained in the same manner as in Example 6-1.

Example 10-2 Synthesis of(1E,6E)-1-[2-benzyloxy-4-(diethylamino)phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 10-3 Synthesis of3-benzyloxy-N,N-diethyl-4-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]aniline

The title compound was obtained in the same manner as in Example 9-2.

Example 11 Synthesis ofN,N-diethyl-4-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-(2-morpholinoethoxy)anilineExample 11-1 Synthesis of(1E,6E)-1-[4-(diethylamino)-2-(2-morpholinoethoxy)phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 11-2 Synthesis ofN,N-diethyl-4-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-(2-morpholinoethoxy)aniline

The title compound was obtained in the same manner as in Example 9-2.

Example 12 Synthesis of2-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-5-(2-pyridylmethoxy)phenolExample 12-1 Synthesis of(1E,6E)-1-[2-hydroxy-4-(2-pyridylmethoxy)phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 12-2 Synthesis of2-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-5-(2-pyridylmethoxy)phenol

The title compound was obtained in the same manner as in Example 9-2.

Example 13 Synthesis of4-[2-[2-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-5-(2-pyridylmethoxy)phenoxy]ethyl]morpholineExample 13-1 Synthesis of2-(2-morpholinoethoxy)-4-(2-pyridylmethoxy)benzaldehyde

To 1.0 g of 2-hydroxy-4-(2-pyridylmethoxy)benzaldehyde were successivelyadded 30 mL of acetonitrile, 4.26 g of cesium carbonate and 0.85 g of4-(2-chloroethyl)morpholine hydrochloride. The mixture was stirred at90° C. for 2 hours. To the reaction mixture, 50 mL of water and 150 mLof AcOEt were added, and the organic layer was separated. The obtainedorganic layer was dried over Na₂SO₄ and concentrated to give 1.56 g ofthe title compound in quantitative yield.

Example 13-2(1E,6E)-1-(1H-indol-6-yl)-7-[2-(2-morpholinoethoxy)-4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 13-3 Synthesis of4-[2-[2-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-5-(2-pyridylmethoxy)phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 9-2.

Example 14 Synthesis of4-[2-[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 14-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-morpholinoethoxy)phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 14-2 Synthesis of4-[2-[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 15 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 15-1 Synthesis of(1E,6E)-1-(1-methylindol-6-yl)-7-[4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 15-2 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1-methylindol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 16 Synthesis of6-[(E)-2-[3-[(E)-2-[2-fluoro-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole Example 16-1 Synthesis of(1E,6E)-1-[2-fluoro-4-(2-pyridylmethoxy)phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 16-2 Synthesis of6-[(E)-2-[3-[(E)-2-[2-fluoro-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole

The title compound was obtained in the same manner as in Example 1-2.

Example 17 Synthesis of1-methyl-6-[(E)-2-[3-[(E)-2-[4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indoleExample 17-1 Synthesis of(1E,6E)-1-(1-methylindol-6-yl)-7-[4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 17-2 Synthesis of1-methyl-6-[(E)-2-[3-[(E)-2-[4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indole

The title compound was obtained in the same manner as in Example 1-2.

Example 18 Synthesis of1-methyl-6-[(E)-2-[3-[(E)-2-[4-(4-methylpiperazin-1-yl)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indoleExample 18-1 Synthesis of(1E,6E)-1-(1-methylindol-6-yl)-7-[4-(4-methylpiperazin-1-yl)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 18-2 Synthesis of1-methyl-6-[(E)-2-[3-[(E)-2-[4-(4-methylpiperazin-1-yl)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indole

The title compound was obtained in the same manner as in Example 1-2.

Example 19 Synthesis of2-[[3-fluoro-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 19-1 Synthesis of(E)-3-[2-fluoro-4-(2-pyridylmethoxy)phenyl]-2-propenoic acid

To 1.8 g of malonic acid were added 18 mL of pyridine, 2.0 g of2-fluoro-4-(2-pyridylmethoxy)benzaldehyde and 0.21 mL of piperidine. Themixture was stirred at 75° C. for 1.5 hours and further stirred at 95°C. for 1 hour. The reaction mixture was cooled with ice, water was addedthereto, and 10% hydrochloric acid was added to adjust the pH to 4. Theresulting precipitate was separated by filtration to give 2.0 g of thetitle compound (85% yield).

Example 19-2 Synthesis of(E)-6-[2-fluoro-4-(2-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione

The title compound was obtained in the same manner as in Example 6-1.

Example 19-3 Synthesis of(1E,6E)-1-[2-fluoro-4-(2-pyridylmethoxy)phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 19-4 Synthesis of2-[[3-fluoro-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 20 Synthesis of2-[[4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 20-1 Synthesis of(E)-6-[4-(2-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione

The title compound was obtained in the same manner as in Example 6-1.

Example 20-2 Synthesis of(1E,6E)-1-(1-methylpyrrol-2-yl)-7-[4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 20-3 Synthesis of2-[[4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 21 Synthesis of4-[2-[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 21-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-morpholinoethoxy)phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 21-2 Synthesis of4-[2-[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 22 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 22-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 22-2 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 23 Synthesis of2-[[4-[(E)-2-[5-[(E)-2-(1,5-dimethylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]methyl]pyridineExample 23-1 Synthesis of(1E,6E)-1-(1,5-dimethylpyrrol-2-yl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 23-2 Synthesis of2-[[4-[(E)-2-[5-[(E)-2-(1,5-dimethylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 24 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(1,3,5-trimethylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 24-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1,3,5-trimethylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 24-2 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(1,3,5-trimethylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 25 Synthesis of2-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-6-methylpyridineExample 25-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(6-methyl-2-pyridyl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 25-2 Synthesis of2-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-6-methylpyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 26 Synthesis of3-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-2-methylpyridineExample 26-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(2-methyl-3-pyridyl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 26-2 Synthesis of3-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-2-methylpyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 27 Synthesis of1-methyl-4-[4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]piperazineExample 27-1 Synthesis of (E)-6-(1-methylpyrrol-2-yl)hex-5-ene-2,4-dione

The title compound was obtained in the same manner as in Example 6-1.

Example 27-2 Synthesis of(1E,6E)-1-[4-(4-methylpiperazin-1-yl)phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 27-3 Synthesis of1-methyl-4-[4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]piperazine

The title compound was obtained in the same manner as in Example 1-2.

Example 28 Synthesis of1-methyl-4-[4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]-1,4-diazepaneExample 28-1 Synthesis of(1E,6E)-1-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 28-2 Synthesis of1-methyl-4-[4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]-1,4-diazepane

The title compound was obtained in the same manner as in Example 1-2.

Example 29 Synthesis of3-[(E)-2-(4-isopropoxy-2-methoxyphenyl)vinyl]-5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazoleExample 29-1 Synthesis of(1E,6E)-1-(4-isopropoxy-2-methoxyphenyl)-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 29-2 Synthesis of3-[(E)-2-(4-isopropoxy-2-methoxyphenyl)vinyl]-5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazole

The title compound was obtained in the same manner as in Example 1-2.

Example 30 Synthesis of1-methyl-4-[2-[4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]ethyl]piperazineExample 30-1 Synthesis of4-[2-(4-methylpiperazin-1-yl)ethyl]benzaldehyde

To 87 mL of a solution of 8.7 g of1-[2-(4-bromophenyl)ethyl]-4-methylpiperazine in THF cooled to −70° C.was added dropwise 21.1 mL of a solution of n-butyllithium (1.6 mol/L)in hexane, and the mixture was stirred at the same temperature for 30minutes. While the reaction mixture was stirred at the same temperature,3.6 mL of N,N-dimethylformamide was added dropwise. The mixture wasstirred at the same temperature for 30 minutes. The cooling bath wasremoved, and the mixture was allowed to warm to −10° C., poured into amixture of 12 mL of 1 N hydrochloric acid and 100 mL of cold water, andsubjected to extraction with CHCl₃. The obtained extract was dried overMgSO₄ and concentrated to give 7.04 g of the title compound (98%).

Example 30-2 Synthesis of(1E,6E)-1-[4-[2-(4-methylpiperazin-1-yl)ethyl]phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 30-3 Synthesis of1-methyl-4-[2-[4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]ethyl]piperazine

The title compound was obtained in the same manner as in Example 1-2.

Example 31 Synthesis of2-[2-[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]pyridineExample 31-1 Synthesis of 2-methoxy-4-[2-(2-pyridyl)ethoxy]benzaldehyde

To a stirring ice-cooled mixture of 5.0 g of4-hydroxy-2-methoxybenzaldehyde, 4.5 g of 2-(2-pyridyl)ethanol and 10.3g of triphenylphosphine was added dropwise 15.8 g of a 40% solution ofdiethyl azodicarboxylate in toluene. The mixture was stirred at roomtemperature for 5 hours. The reaction mixture was concentrated, purifiedby silica gel column chromatography (hexane/acetone system) and furtherpurified by silica gel column chromatography (hexane/AcOEt system) togive 5.84 g of the title compound (69% yield).

Example 31-2 Synthesis of(1E,6E)-1-[2-methoxy-4-[2-(2-pyridyl)ethoxy]phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 31-3 Synthesis of2-[2-[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 32 Synthesis of2-[[3-methyl-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 32-1 Synthesis of 2-methyl-4-(2-pyridylmethoxy)benzoic acidmethyl ester

To 0.85 g of 4-hydroxy-2-methyl benzoic acid methyl ester were added 12mL of acetonitrile, 2.12 g of K₂CO₃ and 0.84 g of2-(chloromethyl)pyridine hydrochloride, and the mixture was stirred at90° C. for 4 hours. The reaction mixture was allowed to cool back toroom temperature and neutralized by the addition of 5% hydrochloricacid. To this, 150 mL of AcOEt was added, and the organic layer wasseparated. The obtained organic layer was washed with saturated brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel column chromatography (hexane/AcOEt system) to give 1.18 g of thetitle compound (89% yield).

Example 32-2 Synthesis of [2-methyl-4-(2-pyridylmethoxy)phenyl]methanol

To 1.0 g of 2-methyl-4-(2-pyridylmethoxy)benzoic acid methyl ester wasadded 8 mL of toluene under argon atmosphere. To the mixture cooled to−78° C., 8.7 mL of a solution of diisobutylaluminium hydride (1.0 mol/L)in toluene was added dropwise. The mixture was stirred at the sametemperature for 6 hours and further stirred at −35° C. for 1 hour. Tothe reaction mixture, a saturated aqueous Rochelle salt solution wasadded, and the mixture was stirred at room temperature for 30 minutes.To this, 150 mL of diethyl ether was added, and the organic layer wasseparated. The obtained organic layer was dried over Na₂SO₄ andconcentrated to give 0.83 g of the title compound (93% yield).

Example 32-3 Synthesis of 2-methyl-4-(2-pyridylmethoxy)benzaldehyde

To 0.72 g of [2-methyl-4-(2-pyridylmethoxy)phenyl]methanol were added 30mL of CHCl₃ and 7.2 g of manganese dioxide, and the mixture was stirredat room temperature for 2 hours. Insoluble matter was filtered off fromthe reaction mixture, and the mother liquor was concentrated to give0.70 g of the title compound (99% yield).

Example 32-4 Synthesis of(1E,6E)-1-[2-methyl-4-(2-pyridylmethoxy)phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 32-5 Synthesis of2-[[3-methyl-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 33 Synthesis of2-[2-[3-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]pyridineExample 33-1 Synthesis of(1E,6E)-1-(1-methylpyrrol-2-yl)-7-[3-[2-(2-pyridyl)ethoxy]phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 33-2 Synthesis of2-[2-[3-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 34 Synthesis of2-[[3,5-dimethoxy-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 34-1 Synthesis of 2,6-dimethoxy-4-(2-pyridylmethoxy)benzaldehyde

The title compound was obtained in the same manner as in Example 32-1.

Example 34-2 Synthesis of(1E,6E)-1-[2,6-dimethoxy-4-(2-pyridylmethoxy)phenyl]-7-(1-methylpyrrol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 34-3 Synthesis of2-[[3,5-dimethoxy-4-[(E)-2-[5-[(E)-2-(1-methylpyrrol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 35 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylimidazol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 35-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1-methylimidazol-2-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 35-2 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(1-methylimidazol-2-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 36 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(3-methylimidazol-4-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 36-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(3-methylimidazol-4-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 36-2 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(3-methylimidazol-4-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 37 Synthesis of2-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]pyridineExample 37-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(2-pyridyl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 37-2 Synthesis of2-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 38 Synthesis of7-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]quinolineExample 38-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(7-quinolyl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 38-2 Synthesis of7-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]quinoline

The title compound was obtained in the same manner as in Example 1-2.

Example 39 Synthesis of2-[[4-[(E)-2-[5-[(E)-2-(2-furyl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]methyl]pyridineExample 39-1 Synthesis of(1E,6E)-1-(2-furyl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 39-2 Synthesis of2-[[4-[(E)-2-[5-[(E)-2-(2-furyl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 40 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(5-methyl-2-furyl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 40-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(5-methyl-2-furyl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 40-2 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(5-methyl-2-furyl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 41 Synthesis of2-[[4-[(E)-2-[5-[(E)-2-(4,5-dimethyl-2-furyl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]methyl]pyridineExample 41-1 Synthesis of(1E,6E)-1-(4,5-dimethyl-2-furyl)-7-[2-methoxy-4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 41-2 Synthesis of2-[[4-[(E)-2-[5-[(E)-2-(4,5-dimethyl-2-furyl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 42 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(2-methylpyrazol-3-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridineExample 42-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(2-methylpyrazol-3-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 42-2 Synthesis of2-[[3-methoxy-4-[(E)-2-[5-[(E)-2-(2-methylpyrazol-3-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]methyl]pyridine

The title compound was obtained in the same manner as in Example 1-2.

Example 43 Synthesis of1-methyl-6-[(E)-2-[3-[(E)-2-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indoleExample 43-1 Synthesis of(1E,6E)-1-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 43-2 Synthesis of1-methyl-6-[(E)-2-[3-[(E)-2-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indole

The title compound was obtained in the same manner as in Example 1-2.

Example 44 Synthesis of6-[(E)-2-[3-[(E)-2-[2-methoxy-4-[2-(2-pyridyl)ethoxy]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindoleExample 44-1 Synthesis of(1E,6E)-1-[2-methoxy-4-[2-(2-pyridyl)ethoxy]phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 44-2 Synthesis of6-[(E)-2-[3-[(E)-2-[2-methoxy-4-[2-(2-pyridyl)ethoxy]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole

The title compound was obtained in the same manner as in Example 1-2.

Example 45 Synthesis of6-[(E)-2-[3-[(E)-2-[2,6-dimethoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole Example 45-1 Synthesis of(1E,6E)-1-[2,6-dimethoxy-4-(2-pyridylmethoxy)phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 45-2 Synthesis of6-[(E)-2-[3-[(E)-2-[2,6-dimethoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole

The title compound was obtained in the same manner as in Example 1-2.

Example 46 Synthesis of6-[(E)-2-[3-[(E)-2-[3-fluoro-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole Example 46-1 Synthesis of(1E,6E)-1-[3-fluoro-4-(2-pyridylmethoxy)phenyl]-7-(1-methylindol-6-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 46-2 Synthesis of6-[(E)-2-[3-[(E)-2-[3-fluoro-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole

The title compound was obtained in the same manner as in Example 1-2.

Example 47 Synthesis of4-[[4-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]methyl]morpholineExample 47-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[4-(morpholinomethyl)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 47-2 Synthesis of4-[[4-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]methyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 48 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]ethyl]morpholineExample 48-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[4-(2-morpholinoethyl)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 48-2 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 49 Synthesis of4-[3-[4-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]propyl]morpholineExample 49-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[4-β-morpholinopropyl)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 49-2 Synthesis of4-[3-[4-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenyl]propyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 50 Synthesis of6-[(E)-2-[3-[(E)-2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1H-indoleExample 50-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 50-2 Synthesis of6-[(E)-2-[3-[(E)-2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1H-indole

The title compound was obtained in the same manner as in Example 1-2.

Example 51 Synthesis of6-[(E)-2-[3-[(E)-2-[4-[2-(4-methylpiperazin-1-yl)ethyl]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1H-indoleExample 51-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[4-[2-(4-methylpiperazin-1-yl)ethyl]phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 51-2 Synthesis of6-[(E)-2-[3-[(E)-2-[4-[2-(4-methylpiperazin-1-yl)ethyl]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1H-indole

The title compound was obtained in the same manner as in Example 1-2.

Example 52 Synthesis of4-[2-[2-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 52-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[2-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 52-2 Synthesis of4-[2-[2-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 53 Synthesis of4-[2-[3-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholineExample 53-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[3-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 53-2 Synthesis of4-[2-[3-[(E)-2-[5-[(E)-2-(1H-indol-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 54 Synthesis of6-[(E)-2-[3-[(E)-2-[2-methoxy-4-[2-(2-pyridyl)ethoxy]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1H-indoleExample 54-1 Synthesis of(1E,6E)-1-(1H-indol-6-yl)-7-[2-methoxy-4-[2-(2-pyridyl)ethoxy]phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 54-2 Synthesis of6-[(E)-2-[3-[(E)-2-[2-methoxy-4-[2-(2-pyridyl)ethoxy]phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1H-indole

The title compound was obtained in the same manner as in Example 1-2.

Example 55 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]ethyl]morpholineExample 55-1 Synthesis of(E)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)hex-5-ene-2,4-dione

The title compound was obtained in the same manner as in Example 6-1.

Example 55-2 Synthesis of(1E,6E)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[2-methoxy-4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 55-3 Synthesis of4-[2-[4-[(E)-2-[5-[(E)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)vinyl]-1H-pyrazol-3-yl]vinyl]-3-methoxyphenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 56 Synthesis of4-[2-[3-methoxy-4-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-morpholinoethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]phenoxy]ethyl]morpholineExample 56-1 Synthesis of(1E,6E)-1,7-bis[2-methoxy-4-(2-morpholinoethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 5-1.

Example 56-2 Synthesis of4-[2-[3-methoxy-4-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-morpholinoethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]phenoxy]ethyl]morpholine

The title compound was obtained in the same manner as in Example 1-2.

Example 57 Synthesis of1-methyl-2-[(E)-2-[3-[(E)-2-[4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indoleExample 57-1 Synthesis of(1E,6E)-1-(1-methylindol-2-yl)-7-[4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 57-2 Synthesis of1-methyl-2-[(E)-2-[3-[(E)-2-[4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indole

The title compound was obtained in the same manner as in Example 1-2.

Example 58 Synthesis of5-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole Example 58-1 Synthesis of(1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1-methylindol-5-yl)hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 58-2 Synthesis of5-[(E)-2-[3-[(E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]-1-methylindole

The title compound was obtained in the same manner as in Example 1-2.

Example 59 Synthesis of1-methyl-6-[(E)-2-[3-[(E)-2-[2-methyl-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indoleExample 59-1 Synthesis of(1E,6E)-1-(1-methylindol-6-yl)-7-[2-methyl-4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione

The title compound was obtained in the same manner as in Example 1-1.

Example 59-2 Synthesis of1-methyl-6-[(E)-2-[3-[(E)-2-[2-methyl-4-(2-pyridylmethoxy)phenyl]vinyl]-1H-pyrazol-5-yl]vinyl]indole

The title compound was obtained in the same manner as in Example 1-2.

The structural formulas and analytical data of the compounds obtained inthe above Examples are shown in the tables below.

Ex.: example; St.: chemical structure; Dat.: analytical data

TABLE 2 St. Ex. Dat. 1-1

¹H NMR (δ, CDCl₃): 2.56-2.61 (m, 4H), 2.82 (t, 2H, J = 5.7 Hz),3.72-3.76 (m, 4H), 4.15 (t, 2H, J = 5.7 Hz), 5.81 (s, 1H), 6.51 (d, 1H,J = 16.0 Hz), 6.56-6.58 (m, 1H), 6.64 (d, 1H, J = 16.0 Hz), 6.92 (d, 2H,J = 8.8 Hz), 7.28-7.30 (m, 1H), 7.40 (dd, 1H, J = 1.3 Hz, 8.2 Hz), 7.50(d, 2H, J = 8.8 Hz), 7.56 (s, 1H), 7.62 (d, 1H, J = 16.0 Hz), 7.63 (d,1H, J = 8.2 Hz), 7.79 (d, 1H, J = 16.0 Hz), 8.30 (s, 1H), 16.07 (brs,1H) MS (EI) m/z 444 (M⁺). 1-2

¹H NMR (δ, CDCl₃): 2.55-2.60 (m, 4H), 2.80 (t, 2H, J = 5.7 Hz),3.72-3.75 (m, 4H), 4.11 (t, 2H, J = 5.7 Hz), 6.52-6.54 (m, 1H), 6.60 (s,1H), 6.87 (d, 2H, J = 8.7 Hz), 6.92 (d, 1H, J = 16.4 Hz), 7.01-7.06 (m,2H), 7.18-7.20 (m, 1H), 7.19 (d, 1H, J = 16.4 Hz), 7.31 (dd, 1H, J = 1.4Hz, 8.3 Hz), 7.40 (d, 2H, J = 8.7 Hz), 7.43-7.45 (m, 1H), 7.60 (d, 1H, J= 8.3 Hz), 8.13 (s, 1H), 9.32-11.42 (br, 1H) MS (EI) m/z 440 (M⁺). 2-1

MS (EI) m/z 479 (M⁺) 2-2

¹H NMR (δ, CDCl₃): 2.61-2.74 (m, 4H), 2.84-2.93 (m, 2H), 3.76-3.83 (m,4H), 3.87 (s, 3H), 4.16-4.22 (m, 2H), 5.97 (s, 2H), 6.48-6.52 (m, 2H),6.58 (s, 1H), 6.79 (d, 1H J = 7.8 Hz), 6.88 (d, 1H, J = 16.5 Hz),6.91-6.97 (m, 2H), 7.00 (d, 1H, J = 16.5 Hz), 7.03 (d, 1H, J = 1.4 Hz),7.29 (d, 1H, J = 16.5 Hz), 7.43 (d, 1H, J = 8.2 Hz) MS (EI) m/z 475(M⁺).

TABLE 3 3-1

MS (EI) m/z 449 (M⁺) 3-2

¹H NMR (δ, CDCl₃): 2.56-2.60 (m, 4H), 2.81 (t, 2H, J = 5.7 Hz), 3.74 (m,4H), 4.14 (t, 2H, J = 5.7 Hz), 5.98 (s, 2H), 6.57 (s, 1H), 6.79 (d, 1H,J = 7.8 Hz), 6.84-6.94 (m, 5H), 6.97-7.04 (m, 3H), 7.40-7.43 (m, 2H),9.48-11.04 (br, 1H) MS (EI) m/z 445 (M⁺).

TABLE 4 4-1

¹H NMR (δ, CDCl₃): 2.29 (s, 3H), 2.47 (brs, 8H), 3.52 (s, 2H), 3.88 (s,3H), 3.91 (s, 3H), 6.94 (d, 1H, J = 7.9 Hz), 7.00 (s, 1H), 7.74 (d, 1H,J = 7.9 Hz) 4-2

¹H NMR (δ, CDCl₃): 2.28 (s, 3H), 2.47 (brs, 8H), 3.49 (s, 2H), 3.87 (s,3H), 4.66 (s, 2H), 6.86-6.92 (m, 2H), 7.20 (d, 1H, J = 7.7 Hz) 4-3

¹H NMR (δ, CDCl₃): 2.30 (s, 3H), 2.48 (brs, 8H), 3.53 (s, 2H), 3.94 (s,3H), 6.97-7.02 (m, 2H), 7.77 (d, 1H, J = 7.7 Hz), 10.42 (s, 1H) 4-4

¹H NMR (δ, DMSO-d₆): 2.16 (s, 3H), 2.37 (brs, 8H), 3.48 (s, 2H), 3.89(s, 3H), 6.14 (s, 1H), 6.47-6.51 (m, 1H), 6.84-6.99 (m, 3H), 7.02 (s,1H), 7.43 (d, 1H, J = 8.3 Hz), 7.48-7.51 (m, 1H), 7.60 (d, 1H, J = 8.3Hz), 7.66-7.74 (m, 2H), 7.79 (d, 1H, J = 15.8 Hz), 7.85 (d, 1H, J = 15.9Hz), 11.41 (brs, 1H) MS (ESI) m/z 459 (M⁺2H)⁺, 915 (2M + H)⁺. 4-5

¹H NMR (δ, CDCl₃): 2.31 (s, 3H), 2.50 (brs, 8H), 3.51 (s, 2H), 3.91 (s,3H), 6.54-6.56 (m, 1H), 6.67 (s, 1H), 6.91-6.94 (m, 2H), 7.05 (d, 1H, J= 16.6 Hz), 7.07 (d, 1H, J = 16.6 Hz), 7.18-7.28 (m, 2H), 7.34 (dd, 1H,J = 1.5 Hz, 8.5 Hz), 7.38 (d, 1H, J = 16.6 Hz), 7.47-7.50 (m, 2H), 7.62(d, 1H, J = 8.0 Hz), 8.21 (brs, 1H)

TABLE 5 5-1

¹H NMR (δ, CDCl₃): 2.56-2.61 (m, 8H), 2.81 (t, 4H, J = 5.7 Hz),3.72-3.76 (m, 8H), 4.15 (t, 4H, J = 5.7 Hz), 5.77 (s, 1H), 6.49 (d, 2H,J = 16.0 Hz), 6.92 (d, 4H, J = 8.9 Hz), 7.50 (d, 4H, J = 8.9 Hz), 7.61(d, 2H, J = 16.0 Hz), 16.00 (brs, 1H) MS (EI) m/z 534 (M⁺). 5-2

¹H NMR (δ, CDCl₃): 2.56-2.61 (m, 8H), 2.81 (t, 4H, J = 5.7 Hz),3.72-3.76 (m, 8H), 4.13 (t, 4H, J = 5.7 Hz), 6.57 (s, 1H), 6.89 (d, 2H,J = 16.4 Hz), 6.89 (d, 4H, J = 8.8 Hz), 7.02 (d, 2H, J = 16.4 Hz), 7.41(d, 4H, J = 8.8 Hz) MS (EI) m/z 530 (M⁺). 6-1

¹H NMR (δ, CDCl₃): 2.16 (s, 3H), 2.56-2.60 (m, 4H), 2.81 (t, 2H, J = 5.7Hz), 3.72-3.76 (m, 4H), 4.14 (t, 2H, J = 5.7 Hz), 5.62 (s, 1H), 6.34 (d,1H, J = 15.7 Hz), 6.89-6.93 (m, 2H), 7.45-7.49 (m, 2H), 7.55 (d, 1H, J =15.8 Hz) MS (ESI) m/z 318(M + H)⁺. 6-2

¹H NMR (δ, CDCl₃): 2.57-2.61 (m, 4H), 2.82 (t, 2H, J = 5.7 Hz), 2.99 (s,3H), 3.10 (s, 3H), 3.72-3.77 (m, 4H), 4.15 (t, 2H, J = 5.7 Hz), 4.74 (s,2H), 5.79 (s, 1H), 6.50 (d, 2H, J = 15.7 Hz), 6.90-6.99 (m, 4H),7.48-7.54 (m, 4H), 7.61 (d, 1H, J = 15.8 Hz), 7.62 (d, 1H, J = 15.8 Hz)MS (ESI) m/z 508 (M + 2H)⁺. 6-3

¹H NMR (δ, DMSO-d₆): 2.45-2.52 (m, 4H), 2.69 (t, 2H, J = 5.8 Hz), 2.85(s, 3H), 3.00 (s, 3H), 3.56-3.60 (m, 4H), 4.10 (t, 2H, J = 5.7 Hz), 4.83(s, 2H), 6.67 (s, 1H), 6.87-7.17 (m, 8H), 7.43-7.52 (m, 4H), 12.89 (s,1H)

TABLE 6 7-1

¹H NMR (δ, CDCl₃): 2.56-2.62 (m, 4H), 2.82 (t, 2H, J = 5.7 Hz),3.72-3.77 (m, 4H), 3.927 (s, 3H), 3.940 (s, 3H), 4.15 (t, 2H, J = 5.6Hz), 5.80 (s, 1H), 6.50 (d, 2H, J = 15.8 Hz), 6.86-6.95 (m, 3H),7.07-7.10 (m, 1H), 7.15 (dd, 1H, J = 1.9, 8.3 Hz), 7.48-7.53 (m, 2H),7.61 (d, 1H, J = 15.8 Hz), 7.62 (d, 1H, J = 15.9 Hz) MS (ESI) m/z 466(M + H)⁺. 7-2

¹H NMR (δ, CDCl₃): 2.57-2.61 (m, 4H), 2.81 (t, 2H, J = 5.8 Hz),3.72-3.77 (m, 4H), 3.876 (s, 3H), 3.884 (s, 3H), 4.11 (t, 2H, J = 5.7Hz), 6.60 (s, 1H), 6.78-7.08 (m, 9H), 7.35-7.40 (m, 2H) 8-1

MS (ESI) m/z 446 (M + H)⁺. 8-2

¹H NMR (δ, DMSO-d₆): 2.45-2.53 (m, 4H), 2.69 (t, 2H, J = 5.6 Hz),3.56-3.61 (m, 4H), 4.08-4.13 (m, 2H), 6.72 (s, 1H), 6.90-7.35 (m, 6H),7.42-7.85 (m, 5H), 8.19-8.26 (m, 1H), 12.49 (brs, 1H), 12.92 (brs, 1H)

TABLE 7 9-1

MS (EI) m/z 402 (M⁺). 9-2

¹H NMR (δ, acetone-d₆): 3.90 (s, 3H), 5.23 (s, 2H), 6.10-6.13 (m, 1H),6.26-6.28 (m, 1H), 6.56 (s, 1H), 6.65 (dd, 1H, J = 2.6 Hz, 8.4 Hz), 6.74(d, 1H, J = 2.6 Hz), 6.77 (d, 1H, J = 16.8 Hz), 6.82-6.84 (m, 1H), 7.03(d, 1H, J = 16.8 Hz), 7.06 (d, 1H, J = 16.8 Hz), 7.29-7.33 (m, 1H), 7.35(d, 1H, J = 16.8 Hz), 7.51 (d, 1H, J = 8.4 Hz), 7.56 (br d, 1H, J =7.7), 7.82 (dt, 1H, J = 1.8 Hz, 7.7 Hz), 8.57-8.60 (m, 1H), 10.33 (brs,1H) MS (EI) m/z 398 (M⁺). 10-1

MS (EI) m/z 241 (M⁺). 10-2

MS (EI) m/z 506 (M⁺). 10-3

¹H NMR (δ, CDCl₃): 1.13 (t, 6H, J = 7.2 Hz), 3.33 (q, 4H, J = 7.2 Hz),3.80 (s, 3H), 5.16 (s, 2H), 6.21 (d, 1H, J = 2.0 Hz), 6.31 (dd, 1H, J =2.0 Hz, 8.7 Hz), 6.46 (d, 1H, J = 3.1 Hz), 6.55 (s, 1H), 6.88 (d, 1H, J= 16.4 Hz), 7.05 (d, 1H, J = 3.1 Hz), 7.09 (d, 1H, J = 16.4 Hz),7.21-7.49 (m, 10H), 7.58 (1H, d, J = 8.2 Hz) MS (EI) m/z 502 (M⁺).

TABLE 8 11-1

MS (EI) m/z 529 (M⁺). 11-2

¹H NMR (δ, CDCl₃): 1.19 (t, 6H, J = 7.2 Hz), 2.66-2.70 (m, 4H), 2.93 (t,2H, J = 5.9 Hz), 3.38 (q, 4H, J = 7.2 Hz), 3.75-3.81 (m, 7H), 4.20 (t,2H, J = 5.9 Hz), 6.19 (d, 1H, J = 2.5 Hz), 6.32 (dd, 1H, J = 2.5 Hz, 8.7Hz), 6.46 (d, 1H, J = 3.1 Hz), 6.55 (s, 1H), 6.88 (d, 1H, J = 16.4 Hz),7.05 (d, 1H, J = 3.1 Hz), 7.10 (d, 1H, J = 16.4 Hz), 7.24 (d, 1H, J =16.4 Hz), 7.30 (d, 1H, J = 16.4 Hz), 7.33 (dd, 1H, J = 1.5 Hz, 8.2 Hz),7.39 (d, 1H, J = 8.7 Hz), 7.43 (brs, 1H), 7.58 (d, 1H, J = 8.2 Hz) MS(EI) m/z 525 (M⁺). 12-1

MS (EI) m/z 452 (M⁺). 12-2

¹H NMR (δ, acetone-d₆): 3.87 (s, 3H), 5.17 (s, 2H), 6.41 (d, 1H, J = 3.1Hz), 6.57-6.61 (m, 2H), 6.69 (s, 1H), 7.09 (d, 1H, J = 16.9 Hz), 7.15(d, 1H, J = 16.4 Hz), 7.23 (d, 1H, J = 3.1 Hz), 7.29-7.33 (m, 2H), 7.34(d, 1H, J = 16.4 Hz), 7.41 (d, 1H, J = 16.9 Hz), 7.48 (d, 1H, J = 8.2Hz), 7.52 (br d, 1H, J = 7.7 Hz), 7.54 (d, 1H, J = 8.7 Hz), 7.56 (brs,1H), 7.81 (dt, 1H, J = 2.1 Hz, 7.7 Hz), 8.56-8.59 (m, 1H), 8.13-9.43(br, 1H), 11.20-12.53 (br, 1H) MS (EI) m/z 448 (M⁺).

TABLE 9 13-1

  ¹H NMR (δ, CDCl₃): 2.56-2.61 (m, 4H), 2.85 (t, 2H, J = 5.6 Hz),3.71-3.74 (m, 4H), 4.18 (t, 2H, J = 5.6 Hz), 5.26 (s, 2H), 6.57-6.59 (m,1H), 6.62-6.65 (m, 1H), 7.24-7.28 (m, 1H), 7.47-7.50 (m, 1H), 7.72-7.76(m, 1H), 7.81 (d, 1H, J = 8.7 Hz), 8.61-8.63 (m, 1H), 10.31 (s, 1H) 13-2

  MS (EI) m/z 551 (M⁺) 13-3

  ¹H NMR (δ, DMSO-d₆): 2.49-2.56 (m, 4H), 2.77-2.82 (m, 2H), 3.59-3.63(m, 4H), 4.17 (t, 2H, J = 5.7 Hz), 5.22 (s, 2H), 6.40-6.44 (m, 1H),6.61-6.69 (m, 2H), 6.75-6.79 (m, 1H), 6.98-7.10 (m, 2H), 7.20-7.31 (m,3H), 7.34-7.40 (m, 2H), 7.46-7.57 (m, 4H), 7.84-7.88 (m, 1H), 8.58-8.61(m, 1H) 11.18 (brs, 1H), 12.87 (brs, 1H) MS (EI) m/z 547 (M⁺).

TABLE 10 14-1

  1H NMR (δ, CDCl₃): 2.56-2.60 (m, 4H), 2.82 (t, 2H, J = 5.8 Hz),3.72-3.76 (m, 4H), 3.83 (s, 3H), 3.88 (s, 3H), 4.15 (t, 2H, J = 5.8 Hz),5.83 (s, 1H), 6.48-6.53 (m, 3H), 6.64 (d, 1H, J = 16.0 Hz), 6.66 (d, 1H,J = 16.0 Hz), 7.12 (d, 1H, J = 3.2 Hz), 7.38 (dd, 1H, J = 1.3, 8.3 Hz),7.47-7.49 (m, 2H), 7.60 (d, 1H, J = 8.3 Hz), 7.81 (d, 1H, J = 16.0 Hz),7.90 (d, 1H, J = 16.0 Hz) MS (EI) m/z 488 (M⁺). 14-2

  1H NMR (δ, CDCl₃): 2.59-2.63 (m, 4H), 2.83 (t, 2H, J = 5.7 Hz),3.75-3.78 (m, 4H), 3.79 (s, 3H), 3.86 (s, 3H), 4.14 (t, 2H, J = 5.7 Hz),6.45-6.50 (m, 3H), 6.64 (s, 1H), 6.99 (d, 1H, J = 16.6 Hz), 7.06 (d, 1H,J = 3.1 Hz), 7.09 (d, 1H, J = 16.5 Hz), 7.24 (s, 1H, J = 16.6 Hz),7.30-7.35 (m, 2H), 7.40-7.42 (m, 1H), 7.45 (d, 1H, J = 9.2 Hz), 7.58 (d,1H, J = 8.2 Hz). MS (EI) m/z 484 (M⁺). 15-1

  MS (EI) m/z 458 (M⁺). 15-2

  1H NMR (δ, CDCl₃): 2.57-2.61 (m, 4H), 2.82 (t, 2H, J = 5.7 Hz),3.73-3.76 (m, 4H), 3.80 (s, 3H), 4.14 (t, 2H, J = 5.7 Hz), 6.46-6.47 (m,1H), 6.61 (s, 1H), 6.88-6.97 (m, 3H), 7.02-7.08 (m, 3H), 7.23 (d, 1H, J= 16.5 Hz), 7.31 (dd, 1H, J = 1.4, 8.3 Hz), 7.40-7.44 (m, 2H), 7.59 (d,1H, J = 8.3 Hz), 7.77 (d, 1H, J = 8.7 Hz) MS (EI) m/z 454 (M⁺).

TABLE 11 16-1

  MS (EI) m/z 454 (M⁺). 16-2

  1H NMR (δ, CDCl₃): 3.80 (s, 3H), 5.21 (s, 2H), 6.47 (dd, 1H, J = 0.7Hz, 3.2 Hz), 6.65 (s, 1H), 6.73 (dd, 1H, J = 2.5 Hz, 12.3 Hz), 6.79 (dd,1H, J = 2.5 Hz, 8.7 Hz), 7.02 (d, 1H, J = 16.7 Hz), 7.05 (d, 1H, J =16.9 Hz), 7.06 (d, 1H, J = 3.0 Hz), 7.16 (d, 1H, J = 16.7 Hz), 7.21-7.26(m, 2H), 7.32 (dd, 1H, J = 1.35 Hz, 8.3 Hz), 7.40 (s, 1H), 7.45-7.51 (m,2H), 7.59 (d, 1H, J = 8.3 Hz), 7.70-7.75 (m, 1H), 8.62 (d, 1H, J = 4.3Hz) MS (EI) m/z 450 (M⁺). 17-1

  1H NMR (δ, CDCl₃): 3.84 (s, 3H), 5.25 (s, 2H), 5.82 (s, 1H), 6.49-6.53(m, 2H), 6.67 (d, 1H, J = 15.7 Hz), 7.00-7.02 (m, 2H), 7.13 (d, 1H, J =3.0 Hz), 7.23-7.27 (m, 1H), 7.39 (dd, 1H, J = 1.2, 8.4 Hz), 7.48-7.53(m, 4H), 7.60-7.64 (m, 2H), 7.71-7.75 (m, 1H), 7.83 (d, 1H, J = 15.7Hz), 8.60-8.63 (m, 1H), 16.11 (brs, 1H). MS (EI) m/z 436 (M⁺). 17-2

  1H NMR (δ, CDCl₃): 3.77 (s, 3H), 5.22 (s, 2H), 6.46 (d, 1H, J = 3.0Hz), 6.62 (s, 1H), 6.91-6.97 (m, 3H), 7.04-7.10 (m, 3H), 7.22-7.27 (m,2H), 7.31 (dd, 1H, J = 1.0, 8.3 Hz), 7.40-7.43 (m, 3H), 7.51-7.53 (m,1H), 7.58 (d, 1H, J = 8.3 Hz), 7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H). MS(EI) m/z 432 (M⁺).

TABLE 12 18-1

  1H NMR (δ, CDCl₃): 2.35 (s, 3H), 2.56 (t, 4H, J = 4.9 Hz), 3.32 (t,4H, J = 4.9 Hz), 3.83 (s, 3H), 5.81 (s, 1H), 6.44-6.51 (m, 2H), 6.65 (d,1H, J = 15.7 Hz), 6.89 (d, 2H, J = 8.6 Hz), 7.12 (d, 1H, J = 2.9 Hz),7.38 (d, 1H, J = 8.3 Hz), 7.44-7.50 (m, 3H), 7.58-7.64 (m, 2H), 7.81 (d,1H, J = 15.7 Hz), 16.15 (brs, 1H) MS (EI) m/z 427 (M⁺). 18-2

  1H NMR (δ, CDCl₃): 2.38 (s, 3H), 2.57-2.64 (m, 4H), 3.24-3.31 (m, 4H),3.80 (s, 3H), 6.45-6.48 (m, 1H), 6.60-6.62 (m, 1H), 6.87-6.92 (m, 3H),6.99-7.10 (m, 3H), 7.20-7.27 (m, 1H), 7.32 (d, 1H, J = 8.5 Hz),7.39-7.43 (m, 3H), 7.57-7.61 (m, 1H) MS (EI) m/z 423 (M⁺).

TABLE 13 19-1

  1H NMR (δ, DMSO-d₆): 5.25 (s, 2H), 6.46 (s, 1H, J = 16.1 Hz),6.92-6.96 (m, 1H), 7.02-7.07 (m, 1H), 7.35-7.39 (m, 1H), 7.52-7.54 (m,1H), 7.59 (d, 1H, J = 16.1 Hz), 7.76-7.80 (m, 1H), 7.83-7.88 (m, 1H),8.58-8.60 (m, 1H), 12.41 (brs, 1H) MS (EI) m/z 273 (M⁺). 19-2

  1H NMR (δ, CDCl₃): 2.16 (s, 3H), 5.23 (s, 2H), 5.63-5.64 (m, 1H),6.44-6.48 (m, 1H), 6.72-6.76 (m, 1H), 6.79-6.82 (m, 1H), 7.25-7.29 (m,1H), 7.42-7.47 (m, 1H), 7.48-7.50 (m, 1H), 7.63 (d, 1H, J = 16.1 Hz),7.72-7.77 (m, 1H), 8.60-8.63 (m, 1H) MS (EI) m/z 313 (M⁺). 19-3

  1H NMR (δ, CDCl₃): 3.74 (s, 3H), 5.23 (s, 2H), 5.72 (s, 1H), 6.19-6.22(m, 1H), 6.37 (d, 1H, J = 15.4 Hz), 6.59 (d, 1H, J = 16.1 Hz), 6.71-6.77(m, 2H), 6.77-6.79 (m, 1H), 6.81 (dd, 1H, J = 2.5 Hz, 8.8 Hz), 7.24-7.28(m, 1H), 7.45-7.51 (m, 2H), 7.61 (d, 1H, J = 15.4 Hz), 7.67 (d, 1H, J =16.1 Hz), 7.72-7.76 (m, 1H), 8.61-8.63 (m, 1H), 16.10 (brs, 1H) MS (EI)m/z 404 (M⁺). 19-4

  1H NMR (δ, CDCl₃): 3.70 (s, 3H), 5.21 (s, 2H), 6.14-6.16 (m, 1H), 6.50(dd, 1H, J = 1.4 Hz, 3.8 Hz), 6.58 (s, 1H), 6.65 (t, 1H, J = 2.1 Hz),6.71-6.81 (m, 3H), 6.94-7.02 (m, 2H), 7.14 (d, 1H, J = 16.7 Hz),7.24-7.27 (m, 1H), 7.47 (t, 1H, J = 8.7 Hz), 7.50 (d, 1H, J = 8.0 Hz),7.71-7.75 (m, 1H), 8.62 (d, 1H, J = 4.9 Hz) MS (EI) m/z 400 (M⁺).

TABLE 14 20-1

  1H NMR (δ, CDCl₃): 2.15 (s, 3H), 5.24 (s, 2H), 5.61 (s, 1H), 6.34 (d,1H, J = 16.0 Hz), 6.99 (d, 2H, J = 8.7 Hz), 7.23 (dd, 1H, J = 5.0 Hz,7.6 Hz), 7.47 (d, 2H, J = 8.7 Hz), 7.48-7.51 (m, 1H), 7.55 (d, 1H, J =16.0 Hz), 7.69-7.73 (m, 1H), 8.60-8.62 (m, 1H), 15.43 (brs, 1H) 20-2

  1H NMR (δ, CDCl₃): 3.74 (s, 3H), 5.25 (s, 2H), 5.71 (s, 1H), 6.19-6.21(m, 1H), 6.37 (d, 1H, J = 15.4 Hz), 6.48 (d, 1H, J = 15.8 Hz), 6.71-6.73(m, 1H), 6.77-6.78 (m, 1H), 7.00 (d, 2H, J = 8.8 Hz), 7.23-7.27 (m, 1H),7.48-7.52 (m, 1H), 7.50 (d, 2H, J = 8.8 Hz), 7.59 (d, 1H, J = 15.8 Hz),7.60 (d, 1H, J = 15.4 Hz), 7.71-7.75 (m, 1H), 8.61 (d, 1H, J = 4.2 Hz)MS (EI) m/z 386 (M⁺). 20-3

  1H NMR (δ, CDCl₃): 3.69 (s, 3H), 5.23 (s, 2H), 6.15 (t, 1H, J = 3.2Hz), 6.49 (dd, 1H, J = 1.5 Hz, 3.7 Hz), 6.54 (s, 1H), 6.64-6.66 (m, 1H),6.76 (d, 1H, J = 16.2 Hz), 6.90 (d, 1H, J = 16.5 Hz), 6.96 (d, 1H, J =16.2 Hz), 6.98 (d, 2H, J = 8.8 Hz), 7.02 (d, 1H, J = 16.5 Hz), 7.22-7.26(m, 1H), 7.42 (d, 2H, J = 8.8 Hz), 7.52 (d, 1H, J = 7.9 Hz), 7.70-7.74(m, 1H), 8.60-8.62 (m, 1H) MS (EI) m/z 382 (M⁺).

TABLE 15 21-1

  MS (EI) m/z 438 (M⁺). 21-2

  1H NMR (δ, CDCl₃): 2.57-2.60 (m, 4H), 2.81 (t, 2H, J = 5.7 Hz), 3.69(s, 3H), 3.73-3.76 (m, 4H), 3.86 (s, 3H), 4.13 (t, 2H, J = 5.7 Hz),6.13-6.15 (m, 1H), 6.47-6.51 (m, 3H), 6.54 (s, 1H), 6.63-6.64 (m, 1H),6.77 (d, 1H, J = 16.0 Hz), 6.95 (d, 1H, J = 16.5 Hz), 6.96 (d, 1H, J =16.0 Hz), 7.29 (d, 1H, J = 16.5 Hz), 7.43 (s, 1H, J = 8.3 Hz) MS (EI)m/z 434 (M⁺). 22-1

  MS (EI) m/z 416 (M⁺). 22-2

  1H NMR (δ, CDCl₃): 3.68 (s, 3H), 3.84 (s, 3H), 5.23 (s, 2H), 6.13-6.15(m, 1H), 6.47 (dd, 1H, J = 1.4, 3.4 Hz), 6.54 (s, 1H), 6.55-6.59 (m,2H), 6.62-6.63 (m, 1H), 6.77 (d, 1H, J = 16.0 Hz), 6.95 (d, 1H, J = 16.5Hz), 6.96 (d, 1H, J = 16.0 Hz), 7.22-7.25 (m, 1H), 7.29 (d, 1H, J = 16.5Hz), 7.42 (d, 1H, J = 8.7 Hz), 7.51-7.53 (m, 1H), 7.70-7.74 (m, 1H),8.60-8.62 (m, 1H) MS (EI) m/z 412 (M⁺).

TABLE 16 23-1

  1H NMR (δ, CDCl₃): 2.28 (s, 3H), 3.59 (s, 3H), 3.86 (s, 3H), 5.25 (s,2H), 5.69 (s, 1H), 5.99 (d, 1H, J = 3.9 Hz), 6.32 (d, 1H, J = 15.5 Hz),6.56-6.61 (m, 3H), 6.66 (d, 1H, J = 3.9 Hz), 7.24-7.28 (m, 1H), 7.46 (d,1H, J = 9.3 Hz), 7.50-7.53 (m, 1H), 7.60 (d, 1H, J = 15.5 Hz), 7.71-7.76(m, 1H), 7.85 (d, 1H, J = 16.2 Hz), 8.60-8.63 (m, 1H) MS (EI) m/z 430(M⁺). 23-2

  1H NMR (δ, CDCl₃): 2.25 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 5.23 (s,2H), 5.90-5.95 (m, 1H), 6.40-6.45 (m, 1H), 6.52-6.61 (m, 3H), 6.71 (d,1H, J = 16.5 Hz), 6.97 (d, 1H, J = 17.0 Hz), 7.03 (d, 1H, J = 16.5 Hz),7.21-7.35 (m, 2H), 7.42 (d, 1H, J = 8.5 Hz), 7.50-7.54 (m, 1H),7.69-7.76 (m, 1H), 8.68-8.64 (m, 1H) MS (EI) m/z 426 (M⁺). 24-1

  1H NMR (δ, CDCl₃): 2.24 (s, 3H), 2.27 (s, 3H), 3.58 (s, 3H), 3.86 (s,3H), 5.24 (s, 2H), 5.70 (s, 1H), 5.86 (s, 1H), 6.18 (d, 1H, J = 15.5Hz), 6.56-6.60 (m, 3H), 7.23-7.27 (m, 1H), 7.46 (d, 1H, J = 9.2 Hz),7.49-7.53 (m, 1H), 7.69-7.75 (m, 2H), 7.84 (d, 1H, J = 16.1 Hz),8.60-8.63 (m, 1H) MS (EI) m/z 444 (M⁺). 24-2

  1H NMR (δ, CDCl₃): 2.22 (s, 3H), 2.23 (s, 3H), 3.54 (s, 3H), 3.86 (s,3H), 5.24 (s, 2H), 5.80 (s, 1H), 6.52-6.60 (m, 4H), 6.97 (d, 1H, J =16.7 Hz), 7.01 (d, 1H, J = 16.7 Hz), 7.23-7.27 (m, 1H), 7.30 (d, 1H, J =16.7 Hz), 7.44 (d, 1H, J = 8.3 Hz), 7.51-7.54 (m, 1H), 7.71-7.75 (m,1H), 8.61-8.63 (m, 1H) MS (EI) m/z 440 (M⁺).

TABLE 17 25-1

  1H NMR (δ, CDCl₃): 2.60 (s, 3H), 3.88 (s, 3H), 5.25 (s, 2H), 5.92 (s,1H), 6.58-6.61 (m, 2H), 6.66 (d, 1H, J = 16.0 Hz), 7.09-7.12 (m, 1H),7.17 (d, 1H, J = 15.5 Hz), 7.20-7.23 (m, 1H), 7.24-7.27 (m, 1H),7.48-7.53 (m, 2H), 7.56-7.61 (m, 2H), 7.71-7.76 (m, 1H), 7.93 (d, 1H, J= 16.0 Hz), 8.61-8.63 (m, 1H), 15.85 (brs, 1H) MS (EI) m/z 428 (M⁺).25-2

  1H NMR (δ, CDCl₃): 2.59 (s, 3H), 3.86 (s, 3H), 5.24 (s, 2H), 6.56-6.60(m, 2H), 6.68 (s, 1H), 6.97 (d, 1H, J = 16.6 Hz), 7.02-7.04 (m, 1H),7.16 (d, 1H, J = 16.2 Hz), 7.23-7.27 (m, 2H), 7.30 (d, 1H, J = 16.6 Hz),7.44 (d, 1H, J = 8.3 Hz), 7.51-7.58 (m, 3H), 7.71-7.75 (m, 1H),8.61-8.63 (m, 1H) MS (EI) m/z 424 (M⁺). 26-1

  MS (EI) m/z 428 (M⁺). 26-2

  1H NMR (δ, CDCl₃): 2.67 (s, 3H), 3.86 (s, 3H), 5.24 (s, 2H), 6.56-6.61(m, 2H), 6.65 (s, 1H), 6.95 (d, 1H, J = 16.4 Hz), 7.00 (d, 1H, J = 16.4Hz), 7.15 (dd, 1H, J = 4.7, 7.9 Hz), 7.23-7.28 (m, 2H), 7.31 (d, 1H, J =16.4 Hz), 7.43 (d, 1H, J = 8.6 Hz), 7.53 (d, 1H, J = 7.9 Hz), 7.74 (dt,1H, J = 1.9, 7.6 Hz), 7.83 (dd, 1H, J = 1.6, 7.9 Hz), 8.40 (dd, 1H, J =1.6, 4.7 Hz), 8.61-8.63 (m, 1H) MS (EI) m/z 424 (M⁺).

TABLE 18 27-1

  1H NMR (δ, CDCl₃): 2.12 (s, 3H), 3.71 (s, 3H), 5.55 (s, 1H), 6.17-6.19(m, 1H), 6.20 (d, 1H, J = 15.3 Hz), 6.65-6.66 (m, 1H), 6.74-6.75 (m,1H), 7.52 (d, 1H, J = 15.3 Hz), 15.63 (brs, 1H) 27-2

  1H NMR (δ, CDCl₃): 2.85 (s, 3H), 3.06 (t, 4H, J = 5.0 Hz), 3.82 (t,4H, J = 5.0 Hz), 4.22 (s, 3H), 6.19 (s, 1H), 6.68-6.70 (m, 1H), 6.85 (d,1H, J = 15.4 Hz), 6.94 (d, 1H, J = 16.0 Hz), 7.19 (dd, 1H, J = 1.3 Hz,3.9 Hz), 7.24-7.26 (m, 1H), 7.38 (d, 2H, J = 8.9 Hz), 7.95 (d, 2H, J =8.9 Hz), 8.07 (d, 1H, J = 16.0 Hz), 8.08 (d, 1H, J = 15.4 Hz), 16.68(brs, 1H) MS (EI) m/z 377 (M⁺). 27-3

  1H NMR (δ, CDCl₃): 2.38 (s, 3H), 2.58-2.64 (m, 4H), 3.28 (t, 4H, J =4.8 Hz), 3.69 (s, 3H), 6.15 (dd, 1H, J = 2.8 Hz, 3.6 Hz), 6.48 (dd, 1H,J = 1.5 Hz, 3.6 Hz), 6.52 (s, 1H), 6.63-6.65 (m, 1H), 6.76 (d, 1H, J =16.2 Hz), 6.86 (d, 1H, J = 16.4 Hz), 6.90 (d, 2H, J = 8.8 Hz), 6.95 (d,1H, J = 16.2 Hz), 6.99 (d, 1H, J = 16.4 Hz), 7.39 (d, 2H, J = 8.8 Hz) MS(EI) m/z 373 (M⁺).

TABLE 19 28-1

  1H NMR (δ, CDCl₃): 2.02 (quint, 2H, J = 5.9 Hz), 2.38 (s, 3H),2.54-2.58 (m, 2H), 2.69-2.73 (m, 2H), 3.52-3.56 (m, 2H), 3.60-3.64 (m,2H), 3.73 (s, 3H), 5.68 (s, 1H), 6.18-6.21 (m, 1H), 6.36 (d, 1H, J =15.5 Hz), 6.40 (d, 1H, J = 15.7 Hz), 6.66-6.70 (m, 3H), 6.75-6.77 (m,1H), 7.42-7.45 (m, 2H), 7.57 (d, 1H, J = 15.5 Hz)Hz), 7.59 (d, 1H, J =15.6 Hz) MS (EI) m/z 391 (M⁺). 28-2

  1H NMR (δ, CDCl₃): 2.00-2.06 (m, 2H), 2.39 (s, 3H), 2.55-2.60 (m, 2H),2.70-2.74 (m, 2H), 3.50-3.54 (m, 2H), 3.59-3.62 (m, 2H), 3.69 (s, 2H),6.14-6.16 (m, 1H), 6.47-6.53 (m, 2H), 6.63-6.69 (m, 3H), 6.78 (d, 1H, J= 16.1 Hz), 6.79 (d, 1H, J = 16.4 Hz), 6.96 (d, 1H, J = 16.1 Hz), 6.98(d, 1H, J = 16.4 Hz), 7.34-7.38 (m, 2H) MS (EI) m/z 387 (M⁺). 29-1

  1H NMR (δ, CDCl₃): 1.36 (d, 6H, J = 5.8 Hz), 3.73 (s, 3H), 3.86 (s,3H), 4.57-4.63 (m, 1H), 5.71 (s, 1H), 6.18-6.20 (m, 1H), 6.36 (d, 1H, J= 15.4 Hz), 6.44 (d, 1H, J = 2.4 Hz), 6.49 (dd, 1H, J = 2.4 Hz, 8.5 Hz),6.59 (d, 1H, J = 15.9 Hz), 6.68-6.70 (m, 1H), 6.74-6.76 (m, 1H), 7.45(d, 1H, J = 8.5 Hz), 7.58 (d, 1H, J = 15.4 Hz), 7.87 (d, 1H, J = 15.9Hz) MS (EI) m/z 367 (M⁺). 29-2

  1H NMR (δ, CDCl₃): 1.35 (d, 6H, J = 6.1 Hz), 3.69 (s, 3H), 3.85 (s,3H), 4.53-4.61 (m, 1H), 6.13-6.15 (m, 1H), 6.45 (d, 1H, J = 2.3 Hz),6.46-6.49 (m, 2H), 6.54 (s, 1H), 6.62-6.64 (m, 1H), 6.77 (d, 1H, J =16.2 Hz), 6.95 (d, 1H, J = 16.7 Hz), 7.01 (d, 1H, J = 16.2 Hz), 7.30 (d,1H, J = 16.7 Hz), 7.41 (d, 1H, J = 8.5 Hz) MS (EI) m/z 363 (M⁺).

TABLE 20 30-1

  1H NMR (δ, CDCl₃): 2.30 (s, 3H), 2.40-2.66 (m, 10H), 2.86-2.90 (m,2H), 7.37 (d, 2H, J = 8.0 Hz), 7.80 (d, 2H, J = 8.0 Hz), 9.98 (s, 1H)30-2

  MS (EI) m/z 405 (M⁺). 30-3

  1H NMR (δ, CDCl₃): 2.30 (s, 3H), 2.43-2.66 (m, 10H), 2.79-2.83 (m,2H), 3.70 (s, 3H), 6.14-6.16 (m, 1H), 6.49 (dd, 1H, J = 1.4 Hz, 3.7 Hz),6.55 (s, 1H), 6.64-6.65 (m, 1H), 6.75 (d, 1H, J = 16.3 Hz), 6.95 (d, 1H,J = 16.5 Hz), 6.98 (d, 1H, J = 16.3 Hz), 7.05 (d, 1H, J = 16.5 Hz), 7.20(d, 2H, J = 8.1 Hz), 7.40 (d, 2H, J = 8.1 Hz) MS (EI) m/z 401 (M⁺).

TABLE 21 31-1

  MS (EI) m/z 257 (M⁺). 31-2

  1H NMR (δ, CDCl₃): 3.28 (t, 2H, J = 6.6 Hz), 3.73 (s, 3H), 3.86 (s,3H), 4.42 (t, 2H, J = 6.6 Hz), 5.71 (s, 1H), 6.17-6.21 (m, 1H), 6.36 (d,1H, J = 15.4 Hz), 6.45 (d, 1H, J = 2.0 Hz), 6.53 (dd, 1H, J = 2.0 Hz,8.6 Hz), 6.59 (d, 1H, J = 16.0 Hz), 6.90 (d, 1H, J = 3.68 Hz), 6.75 (s,1H), 7.13-7.18 (m, 1H), 7.24-7.28 (m, 1H), 7.45 (d, 1H, J = 8.6 Hz),7.58 (d, 1H, J = 15.4 Hz), 7.60-7.66 (m, 1H), 7.87 (d, 1H, J = 16.0 Hz),8.57 (d, 1H, J = 4.7 Hz), 16.18 (brs, 1H) MS (EI) m/z 430 (M⁺). 31-3

  1H NMR (δ, CDCl₃): 3.28 (t, 2H, J = 6.7 Hz), 3.70 (s, 3H), 3.84 (s,3H), 4.40 (t, 2H, J = 6.7 Hz), 6.15 (t, 1H, J = 3.3 Hz), 6.45 (d, 1H, J= 2.2 Hz), 6.48-6.52 (m, 2H), 6.55 (s, 1H), 6.63-6.65 (m, 1H), 6.77 (d,1H, J = 16.5 Hz), 6.94 (d, 1H, J = 16.9 Hz), 6.99 (d, 1H, J = 16.5 Hz),7.17 (dd, 1H, J = 5.1 Hz, 7.45 Hz), 7.25-7.32 (m, 2H), 7.41 (d, 1H, J =8.6 Hz), 7.62-7.66 (m, 1H), 8.56-8.58 (m, 1H) MS (EI) m/z 426 (M⁺).

TABLE 22 32-1

  1H NMR (δ, CDCl₃): 2.59 (s, 3H), 3.85 (s, 3H), 5.24 (s, 2H), 6.82 (dd,1H, J = 2.5 Hz, 8.8 Hz), 6.85 (d, 1H, J = 2.5 Hz), 7.22-7.26 (m, 1H),7.48-7.51 (m, 1H), 7.70-7.74 (m, 1H), 7.93 (d, 1H, J = 8.7 Hz),8.60-8.62 (m, 1H) MS (EI) m/z 257 (M⁺). 32-2

  1H NMR (δ, CDCl₃): 2.36 (s, 3H), 4.64 (s, 2H), 5.19 (s, 2H), 6.78 (dd,1H, J 2.7 Hz, 8.4 Hz), 6.85 (d, 1H, J = 2.6 Hz), 7.21-7.25 (m, 2H),7.50-7.53 (m, 1H), 7.69-7.73 (m, 1H), 8.58-8.61 (m, 1H) MS (EI) m/z 229(M⁺). 32-3

  1H NMR (δ, CDCl₃): 2.65 (s, 3H), 5.27 (s, 2H), 6.86 (d, 1H, J = 2.4Hz), 6.93 (dd, 1H, J = 2.6 Hz, 8.5 Hz), 7.24-7.27 (m, 1H), 7.48-7.50 (m,1H), 77.1-7.77 (m, 2H), 8.61-8.63 (m, 1H), 10.12 (s, 1H) MS (EI) m/z 227(M⁺). 32-4

  1H NMR (δ, CDCl₃): 2.44 (s, 3H), 3.74 (s, 3H), 5.23 (s, 2H), 5.70 (s,1H), 6.19-6.21 (m, 1H), 6.37 (d, 1H, J = 15.5 Hz), 6.43 (d, 1H, J = 15.5Hz), 6.71-6.73 (m, 1H), 6.77-6.78 (m, 1H), 6.83-6.86 (m, 2H), 7.22-7.27(m, 1H), 7.49-7.52 (m, 1H), 7.55-7.58 (m, 1H), 7.60 (d, 1H, J = 15.5Hz), 7.70-7.74 (m, 1H), 7.86 (d, 1H, J = 15.6 Hz), 8.60-8.62 (m, 1H) MS(EI) m/z 400 (M⁺).

TABLE 23 32-5

  1H NMR (δ, CDCl₃): 2.40 (s, 3H), 3.70 (s, 3H), 5.22 (s, 2H), 6.15-6.16(m, 1H), 6.49 (dd, 1H, J = 1.6 Hz, 3.8 Hz), 6.55 (s, 1H), 6.64-6.66 (m,1H), 6.77 (d, 1H, J = 16.3 Hz), 6.80-6.85 (m, 3H), 6.96 (d, 1H, J = 16.3Hz), 7.21-7.25 (m, 2H), 7.49-7.53 (m, 2H), 7.70-7.74 (m, 1H), 8.60-8.62(m, 1H) MS (EI) m/z 396 (M⁺).

TABLE 24 33-1

  1H NMR (δ, CDCl₃): 3.30 (t, 2H, J = 6.6 Hz), 3.74 (s, 3H), 4.42 (t,2H, J = 6.6 Hz), 5.73 (s, 1H), 6.20-6.22 (m, 1H), 6.38 (d, 1H, J = 15.3Hz), 6.56 (d, 1H, J = 15.9 Hz), 6.72-6.74 (m, 1H), 6.78-6.79 (m, 1H),6.90-6.93 (m, 1H), 7.06-7.08 (m, 1H), 7.11-7.13 (m, 1H), 7.16-7.20 (m,1H), 7.25-7.31 (m, 2H), 7.56 (d, 1H, J = 15.8 Hz), 7.62 (d, 1H, J = 15.6Hz), 7.63-7.67 (m, 1H), 8.56-8.59 (m, 1H), 16.07 (brs, 1H). MS (EI) m/z400 (M⁺). 33-2

  1H NMR (δ, CDCl₃): 3.31 (t, 2H, J = 6.6 Hz), 3.70 (s, 3H), 4.40 (t,2H, J = 6.6 Hz), 6.14-6.17 (m, 1H), 6.49-6.52 (m, 1H), 6.57 (s, 1H),6.64-6.67 (m, 1H), 6.73-6.78 (m, 1H), 6.81-6.85 (m, 1H), 6.98 (d, 1H, J= 16.2 Hz), 7.01-7.08 (m, 4H), 7.17-7.21 (m, 1H), 7.22-7.28 (m, 1H),7.30-7.34 (m, 1H), 7.64-7.69 (m, 1H), 8.56-8.59 (m, 1H) MS (EI) m/z 396(M⁺).

TABLE 25 34-1

  1H NMR (δ, CDCl₃): 3.85 (s, 6H), 50028 (s, 2H), 6.20 (s, 2H),7.25-7.28 (m, 1H), 7.51 (d, 1H, J = 7.8 Hz), 7.73-7.77 (m, 1 H),8.60-8.62 (m, 1 H), 10.35 (s, 1H) MS (EI) m/z 273 (M⁺). 34-2

  1H NMR (δ, CDCl₃): 3.72 (s, 3H), 3.85 (s, 6H), 5.25 (s, 2H), 5.71 (s,1H), 6.17-6.19 (m, 1H), 6.23 (s, 2H), 6.36 (d, 1H, J = 15.4 Hz),6.66-6.68 (m, 1H), 6.73-6.75 (m, 1H), 6.97 (d, 1H, J = 16.0 Hz),7.23-7.26 (m, 1H), 7.51 (d, 1H, J = 7.7 Hz), 7.56 (d, 1H, J = 15.4 Hz),7.71-7.75 (m, 1H), 8.03 (d, 1H, J = 16.0 Hz), 8.61 (d, 1H, J = 4.5 Hz),16.26 (brs, 1H) MS (EI) m/z 446 (M⁺). 34-3

  1H NMR (δ, CDCl₃): 3.69 (s, 3H), 3.84 (s, 6H), 5.24 (s, 2H), 6.13-6.15(m, 1H), 6.26 (s, 2H), 6.47 (dd, 1H, J = 1.6 Hz, 3.7 Hz), 6.54 (s, 1H),6.61-6.63 (m, 1H), 6.80 (d, 1H, J = 16.2 Hz), 6.97 (d, 1H, J = 16.2 Hz),7.22-7.26 (m, 1H), 7.34 (s, 2H), 7.53 (d, 1H, J = 7.9 Hz), 7.71-7.75 (m,1H), 8.61 (d, 1H, J = 5.0 Hz) MS (EI) m/z 442 (M⁺).

TABLE 26 35-1

  1H NMR (δ, CDCl₃): 3.76 (s, 3H), 3.87 (s, 3H), 5.25 (s, 2H), 5.81 (s,1H), 6.58-6.61 (m, 2H), 6.64 (d, 1H, J = 16.0 Hz), 6.95-6.96 (m, 1H),7.04 (d, 1H, J = 15.1 Hz), 7.16-7.17 (m, 1H), 7.22-7.26 (m, 1H), 7.44(d, 1H, J = 15.1 Hz), 7.47-7.52 (m, 2H), 7.70-7.74 (m, 1H), 7.93 (d, 1H,J = 16.0 Hz), 8.60-8.62 (m, 1H), 15.93 (brs, 1H) MS (EI) m/z 417 (M⁺).35-2

  1H NMR (δ, CDCl₃): 3.71 (s, 3H), 3.85 (s, 3H), 5.23 (s, 2H), 6.56-6.60(m, 3H), 6.86-6.88 (m, 1H), 6.96 (d, 1H, J = 16.8 Hz), 6.97 (d, 1H, J =16.1 Hz), 7.09-7.11 (m, 1H), 7.22-7.25 (m, 1H), 7.29 (d, 1H, J = 16.8Hz), 7.42 (d, 1H, J = 8.3 Hz), 7.46 (d, 1H, J = 16.1 Hz), 7.51-7.53 (m,1H), 7.70-7.74 (m, 1H), 8.59-8.62 (m, 1H) MS (EI) m/z 413 (M⁺). 36-1

  MS (EI) m/z 417 (M⁺). 36-2

  1H NMR (δ, CDCl₃): 3.70 (s, 3H), 3.86 (s, 3H), 5.24 (s, 2H), 6.56-6.60(m, 3H), 6.89-6.90 (m, 2H), 6.93 (d, 1H, J = 16.5 Hz), 7.23-7.31 (m,3H), 7.42 (d, 1H, J = 8.2 Hz), 7.43-7.44 (m, 1H), 7.51-7.54 (m, 1H),7.71-7.75 (m, 1H), 8.61-8.63 (m, 1H) MS (EI) m/z 413 (M⁺).

TABLE 27 37-1

  MS (EI) m/z 414 (M⁺). 37-2

  1H NMR (δ, CDCl₃): 3.85 (s, 3H), 5.24 (s, 2H), 6.56-6.59 (m, 2H), 6.66(s, 1H), 6.97 (d, 1H, J = 16.5 Hz), 7.13-7.18 (m, 2H), 7.22-7.25 (m,1H), 7.30 (d, 1H, J = 16.5 Hz), 7.37-7.40 (m, 1H), 7.43 (d, 1H, J = 8.3Hz), 7.51-7.53 (m, 1H), 7.56 (d, 1H, J = 16.1 Hz), 7.63-7.67 (m, 1H),7.70-7.74 (m, 1H), 8.59-8.62 (m, 2H) MS (EI) m/z 410 (M⁺). 38-1

  MS (EI) m/z 464 (M⁺). 38-2

  1H NMR (δ, Acetone-d₆): 3.92 (s, 3H), 5.24 (s, 2H), 6.67 (dd, 1H, J =2.6, 8.4 Hz), 6.76 (d, 1H, J = 2.6 Hz), 6.80 (s, 1H), 7.09 (d, 1H, J =16.7 Hz), 7.30-7.33 (m, 1H), 7.37-7.49 (m, 4H), 7.54 (d, 1H, J = 9.0Hz), 7.66-7.68 (d, 1H, J = 8.4 Hz), 7.80-7.84 (m, 1H), 7.90-7.95 (m,2H), 8.09-8.11 (m, 1H), 8.26-8.29 (m, 1H), 8.58-8.60 (m, 1H), 8.89 (dd,1H, J = 1.9, 3.9 Hz) MS (EI) m/z 460 (M⁺).

TABLE 28 39-1

  1H NMR (δ, CDCl₃): 3.87 (s, 3H), 5.25 (s, 2H), 5.78 (s, 1H), 6.46-6.48(m, 1H), 6.51 (d, 1H, J = 15.4 Hz), 6.57-6.61 (m, 3H), 6.62 (d, 1H, J =15.4 Hz), 7.22-7.26 (m, 1H), 7.39 (d, 1H, J = 15.4 Hz), 7.45-7.49 (m,2H), 7.50 (d, 1H, J = 7.7 Hz), 7.70-7.74 (m, 1H), 7.90 (d, 1H, J = 15.4Hz), 8.61 (d, 1H, J = 4.5 Hz) MS (EI) m/z 403 (M⁺). 39-2

  1H NMR (δ, CDCl₃): 3.85 (s, 3H), 5.24 (s, 2H), 6.37-6.39 (m, 1H),6.41-6.42 (m, 1H), 6.55-6.59 (m, 3H), 6.93-6.98 (m, 3H), 7.23-7.26 (m,1H), 7.32 (d, 1H, J = 16.6 Hz), 7.39 (d, 1H, J = 1.6 Hz), 7.42 (d, 1H, J= 8.4 Hz), 7.53 (d, 1H, J = 7.9 Hz), 7.71-7.75 (m, 1H), 8.60-8.62 (m,1H) MS (EI) m/z 399 (M⁺). 40-1

  1H NMR (δ, CDCl₃): 2.36 (s, 3H), 3.86 (s, 3H), 5.24 (s, 2H), 5.75 (s,1H), 6.07-6.09 (m, 1H), 6.43 (d, 1H, J = 15.4 Hz), 6.49-6.50 (m, 1H),6.57-6.62 (m, 3H), 7.22-7.26 (m, 1H), 7.33 (d, 1H, J = 15.4 Hz),7.45-7.48 (m, 1H), 7.50 (d, 1H, J = 7.7 Hz), 7.70-7.74 (m, 1H), 7.88 (d,1H, J = 16.0 Hz), 8.60-8.62 (m, 1H), 16.02 (brs, 1H) MS (EI) m/z 417(M⁺). 40-2

  1H NMR (δ, CDCl₃): 2.33 (s, 3H), 3.85 (s, 3H), 5.23 (s, 2H), 5.99-6.01(m, 1H), 6.24 (d, 1H, J = 3.15 Hz), 6.53 (s, 1H), 6.56-6.59 (m, 2H),6.79 (d, 1H, J = 16.2 Hz), 6.87 (d, 1H, J = 16.2 Hz), 6.95 (d, 1H, J =16.6 Hz), 7.21-7.25 (m, 1H), 7.28 (d, 1H, J = 16.6 Hz), 7.43 (d, 1H, J =8.3 Hz), 7.52 (d, 1H, J = 7.9 Hz), 7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H)MS (EI) m/z 413 (M⁺).

TABLE 29 41-1

  1H NMR (δ, CDCl₃): 1.95 (s, 3H), 2.27 (s, 3H), 3.86 (s, 3H), 5.25 (s,2H), 5.74 (s, 1H), 6.38-6.42 (m, 2H), 6.57-6.62 (m, 3H), 7.23-7.31 (m,2H), 7.47 (d, 1H, J = 9.3 Hz), 7.49-7.53 (m, 1H), 7.71-7.75 (m, 1H),7.88 (d, 1H, J = 16.3 Hz), 8.59-8.63 (m, 1H) MS (EI) m/z 431 (M⁺). 41-2

  1H NMR (δ, CDCl₃): 1.94 (s, 3H), 2.24 (s, 3H), 3.85 (s, 3H), 5.23 (s,2H), 6.16 (s, 1H), 6.53-6.59 (m, 3H), 6.78 (d, 1H, J = 16.4 Hz), 6.83(d, 1H, J = 16.4 Hz), 6.96 (d, 1H, J = 16.8 Hz), 7.22-7.26 (m, 1H), 7.30(d, 1H, J = 16.8 Hz), 7.43 (d, 1H, J = 8.5 Hz), 7.51-7.53 (m, 1H),7.70-7.74 (m, 1H), 8.60-8.62 (m, 1H) MS (EI) m/z 427 (M⁺). 42-1

  MS (EI) m/z 417 (M⁺). 42-2

  1H NMR (δ, CDCl₃): 3.85 (s, 3H), 3.95 (s, 3H), 5.24 (s, 2H), 6.47 (d,1H, J = 2.0 Hz), 6.57 (dd, 1H, J = 2.4, 8.6 Hz), 6.59 (d, 1H, J = 2.4Hz), 6.60 (s, 1H), 6.93 (d, 1H, J = 16.7 Hz), 6.97 (d, 1H, J = 16.3 Hz),7.03 (d, 1H, J = 16.3 Hz), 7.23-7.27 (m, 1H), 7.31 (d, 1H, J = 16.7 Hz),7.41 (d, 1H, J = 8.3 Hz), 7.44 (d, 1H, J = 2.0 Hz), 7.51-7.54 (m, 1H),7.71-7.75 (m, 1H), 8.61-8.63 (m, 1H) MS (EI) m/z 413 (M⁺).

TABLE 30 43-1

  1H NMR (δ, CDCl₃): 2.00-2.06 (m, 2H), 2.39 (s, 3H), 2.55-2.59 (m, 2H),2.71-2.74 (m, 2H), 3.53-3.56 (m, 2H), 3.61-3.64 (m, 2H), 3.83 (s, 3H),5.79 (s, 1H), 6.43 (d, 1H, J = 15.5 Hz), 6.48-6.50 (m, 1H), 6.65 (d, 1H,J = 15.8 Hz), 6.67-6.70 (m, 2H), 7.12 (d, 1H, J = 3.1 Hz), 7.37-7.40 (m,1H), 7.43-7.49 (m, 3H), 7.59-7.64 (m, 2H), 7.80 (d, 1H, J = 15.7 Hz) MS(EI) m/z 441 (M⁺). 43-2

  1H NMR (δ, CDCl₃): 2.01-2.07 (m, 2H), 2.39 (s, 3H), 2.56-2.61 (m, 2H),2.71-2.75 (m, 2H), 3.51-3.54 (m, 2H), 3.60-3.63 (m, 2H), 3.81 (s, 3H),6.46-6.48 (m, 1H), 6.59 (s, 1H), 6.66-6.68 (m, 2H), 6.82 (d, 1H, J =16.5 Hz), 7.00 (d, 1H, J = 16.4 Hz), 7.05-7.10 (m, 2H), 7.23 (d, 1H, J =16.4 Hz), 7.31-7.34 (m, 1H), 7.36-7.39 (m, 2H), 7.41-7.43 (m, 1H), 7.59(d, 1H, J = 8.1 Hz) MS (EI) m/z 437 (M⁺). 44-1

  MS (EI) m/z 480 (M⁺). 44-2

  1H-NMR (CDCl₃): δ 3.28 (t, 2H, J = 6.7 Hz), 3.79 (s, 3H), 3.84 (s,3H), 4.40 (t, 2H, J = 6.7 Hz), 6.45-6.47 (m, 2H), 6.51 (dd, 1H, J = 2.3Hz, 8.3 Hz), 6.62 (s, 1H), 6.96 (d, 1H, J = 16.5 Hz), 7.05 (d, 1H, J =3.0 Hz), 7.08 (d, 1H, J = 16.5 Hz), 7.14-7.18 (m, 1H), 7.23 (d, 1H, J =16.5 Hz), 7.26-7.29 (m, 1H), 7.29-7.33 (m, 2H), 7.40 (brs, 1H), 7.42 (d,1H, J = 8.6 Hz), 7.58 (d, 1H, J = 8.3 Hz), 7.61-7.65 (m, 1H), 8.56-8.58(m, 1H) MS (EI) m/z 476 (M⁺).

TABLE 31 45-1

  1H NMR (δ, CDCl₃): 3.82 (s, 3H), 3.86 (s, 6H), 5.25 (s, 2H), 5.82 (s,1H), 6.24 (s, 2H), 6.48 (d, 1H, J = 3.2 Hz), 6.66 (d, 1H, J = 15.4 Hz),7.01 (d, 1H, J = 16.0 Hz), 7.11 (d, 1H, J = 3.2 Hz), 7.23-7.26 (m, 1H),7.37 (d, 1H, J = 1.3 Hz, 8.4 Hz), 7.47 (s, 1H), 7.52 (d, 1H, J = 7.7Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.71-7.75 (m, 1H), 7.79 (d, 1H, J = 15.4Hz), 8.07 (d, 1H, J = 16.0 Hz), 8.60-8.62 (m, 1H), 16.23 (brs, 1H) MS(EI) m/z 496 (M⁺). 45-2

  1H NMR (δ, CDCl₃): 3.79 (s, 3H), 3.85 (s, 6H), 5.24 (s, 2H), 6.26 (s,2H), 6.45 (d, 1H, J = 3.2 Hz), 6.63 (s, 1H), 7.04 (d, 1H, J = 2.75 Hz),7.11 (d, 1H, J = 16.1 Hz), 7.22-7.27 (m, 2H), 7.31 (dd, 1H, J = 1.4 Hz,8.3 Hz), 7.37 (s, 2H), 7.41 (s, 1H), 7.53 (d, 1H, J = 7.75 Hz), 7.57 (d,1H, J = 8.3 Hz), 7.71-7.75 (m, 1H), 8.60-8.62 (m, 1H) MS (EI) m/z 492(M⁺). 46-1

  MS (EI) m/z 454 (M⁺). 46-2

  MS (EI) m/z 450 (M⁺).

TABLE 32 47-1

  1H NMR (δ, CDCl₃): 2.44-2.48 (m, 4H), 3.52 (s, 2H), 3.70-3.74 (m, 4H),5.84 (s, 1H), 6.57-6.59 (m, 1H), 6.62 (d, 1H, J = 15.9 Hz), 6.66 (d, 1H,J = 15.8 Hz), 7.29-7.31 (m, 1H), 7.35-7.38 (m, 2H), 7.39-7.42 (m, 1H),7.50-7.53 (m, 2H), 7.57-7.58 (m, 1H), 7.63-7.67 (m, 2H), 7.81 (d, 1H, J= 15.7 Hz), 8.31 (brs, 1H), 16.03 (brs, 1H) MS (EI) m/z 414 (M⁺). 47-2

  1H NMR (δ, CDCl₃): 2.44-2.48 (m, 4H), 3.51 (s, 2H), 3.70-3.74 (m, 4H),6.54-6.55 (m, 1H), 6.63 (s, 1H), 7.03 (d, 1H, J = 16.3 Hz), 7.04 (d, 1H,J = 16.5 Hz), 7.09 (d, 1H, J = 16.5 Hz), 7.20 (d, 1H, J = 16.2 Hz),7.21-7.23 (m, 1H), 7.30-7.34 (m, 3H), 7.44-7.47 (m, 3H), 7.61 (d, 1H, J= 8.3 Hz), 8.16 (brs, 1H) MS (EI) m/z 410 (M⁺). 48-1

  1H NMR (δ, CDCl₃): 2.49-2.56 (m, 4H), 2.59-2.64 (m, 2H), 2.81-2.86 (m,2H), 3.72-3.76 (m, 4H), 5.83 (s, 1H), 6.56-6.58 (m, 1H), 6.59 (d, 1H, J= 16.0 Hz), 6.65 (d, 1H, J = 16.0 Hz), 7.24 (d, 2H, J = 8.2 Hz),7.28-7.30 (m, 1H), 7.39-7.41 (m, 1H), 7.48 (d, 2H, J = 8.2 Hz), 7.57 (s,1H), 7.61-7.65 (m, 2H), 7.80 (d, 1H, J = 16.0 Hz), 8.30 (brs, 1H), 16.00(brs, 1H) MS (EI) m/z 428 (M⁺). 48-2

  1H NMR (δ, DMSO-d₆): 2.41-2.44 (m, 4H), 2.49-2.55 (m, 2H), 2.74 (t,2H, J = 7.7 Hz), 3.56-3.60 (m, 4H), 6.42 (brs, 1H), 6.73 (s, 1H),6.96-7.39 (m, 8H), 7.43-7.56 (m, 4H), 11.04-11.17 (m, 1H), 12.88 (s, 1H)MS (EI) m/z 424 (M⁺).

TABLE 33 49-1

  1H NMR (δ, CDCl₃): 1.81-1.88 (m, 2H), 2.35-2.51 (m, 6H), 2.68 (t, 2H,J = 7.7 Hz), 3.70-3.77 (m, 4H), 5.83 (s, 1H), 6.57-6.62 (m, 2H), 6.66(d, 1H, J = 15.9 Hz), 7.20-7.23 (m, 2H), 7.30-7.31 (m, 1H), 7.41 (dd,1H, J = 1.4, 8.2 Hz), 7.47-7.50 (m, 2H), 7.57-7.58 (m, 1H), 7.62-7.66(m, 2H), 7.81 (d, 1H, J = 15.9 Hz), 8.32 (brs, 1H) MS (EI) m/z 442 (M⁺).49-2

  1H NMR (δ, CDCl₃): 1.81-1.88 (m, 2H), 2.39 (t, 2H, J = 7.6 Hz),2.44-2.49 (m, 4H), 2.65 (t, 2H, J = 7.7 Hz), 3.72-3.76 (m, 4H),6.54-6.56 (m, 1H), 6.64 (s, 1H), 7.00-7.06 (m, 2H), 7.08 (d, 1H, J =16.6 Hz), 7.16-7.23 (m, 4H), 7.33 (dd, 1H, J = 1.2, 8.5 Hz), 7.40-7.43(m, 2H), 7.47-7.48 (m, 1H), 7.61 (d, 1H, J = 8.3 Hz), 8.19 (brs, 1H) MS(EI) m/z 438 (M⁺). 50-1

  1H NMR (δ, CDCl₃): 2.29 (s, 3H), 2.35-2.61 (m, 8H), 3.53 (s, 2H), 5.84(s, 1H), 6.57-6.59 (m, 1H), 6.61 (d, 1H, J = 15.9 Hz), 6.66 (d, 1H, J =15.8 Hz), 7.29-7.31 (m, 1H), 7.34-7.37 (m, 2H), 7.40-7.42 (m, 1H),7.49-7.52 (m, 2H), 7.56-7.58 (m, 1H), 7.64 (d, 1H, J = 8.3 Hz), 7.65 (d,1H, J = 15.9 Hz), 7.81 (d, 1H, J = 15.7 Hz), 8.33 (brs, 1H), 16.03 (brs,1H) MS (EI) m/z 427 (M⁺). 50-2

  1H NMR (δ, CDCl₃): 2.29 (s, 3H), 2.40-2.57 (m, 8H), 3.51 (s, 2H),6.54-6.56 (m, 1H), 6.63 (s, 1H), 7.02 (d, 1H, J = 16.4 Hz), 7.03 (d, 1H,J = 16.5 Hz), 7.08 (d, 1H, J = 16.5 Hz), 7.19 (d, 1H, J = 16.5 Hz),7.20-7.23 (m, 1H), 7.29-7.34 (m, 3H), 7.42-7.48 (m, 3H), 7.61 (d, 1H, J= 8.3 Hz), 8.23 (brs, 1H) MS (EI) m/z 423 (M⁺).

TABLE 34 51-1

  1H NMR (δ, CDCl₃): 2.30 (s, 3H), 2.40-2.65 (m, 10H), 2.80-2.85 (m,2H), 5.83 (s, 1H), 6.56-6.61 (m, 2H), 6.65 (d, 1H, J = 15.9 Hz), 7.23(d, 2H, J = 8.1 Hz), 7.28-7.30 (m, 1H), 7.40 (dd, 1H, J = 1.5 Hz, 8.05Hz), 7.47 (d, 2H, J = 8.1 Hz), 7.56 (s, 1H), 7.61-7.65 (m, 2H), 7.80 (d,1H, J = 15.9 Hz), 8.34 (brs, 1H), 15.96 (brs, 1H) MS (EI) m/z 441 (M⁺).51-2

  1H NMR (δ, CDCl₃): 2.32 (s, 3H), 2.41-2.69 (m, 10H), 2.78-2.85 (m,2H), 6.54-6.56 (m, 1H), 6.63 (s, 1H), 7.01 (d, 1H, J = 16.5 Hz), 7.03(d, 1H, J = 16.4 Hz), 7.07 (d, 1H, J = 16.5 Hz), 7.16-7.22 (m, 3H),7.22-7.24 (m, 1H), 7.33 (dd, 1H, J = 1.3 Hz, 8.2 Hz), 7.42 (d, 2H, J =8.1 Hz), 7.48 (brs, 1H), 7.62 (d, 1H, J = 8.2 Hz), 8.19 (brs, 1H) MS(EI) m/z 437 (M⁺). 52-1

  1H NMR (δ, CDCl₃): 2.63 (t, 4H, J = 4.8 Hz), 2.89 (t, 2H, J = 5.8 Hz),3.76 (t, 4H, J = 4.8 Hz), 4.20 (t, 2H, J = 5.8 Hz), 5.83 (s, 1H),6.56-6.58 (m, 1H), 6.65 (d, 1H, J = 16.0 Hz), 6.76 (d, 1H, J = 16.0 Hz),6.93 (d, 1H, J = 8.0 Hz), 6.96-7.00 (m, 1H), 7.28-7.34 (m, 2H), 7.40(dd, 1H, J = 1.5 Hz, 8.0 Hz), 7.54-7.58 (m, 2H), 7.64 (d, 1H, J = 8.25Hz), 7.80 (d, 1H, J = 16.0 Hz), 7.97 (d, 1H, J = 16.0 Hz), 8.31 (brs,1H), 16.01 (brs, 1H) MS (EI) m/z 444 (M⁺). 52-2

  1H NMR (δ, CDCl₃): 2.62 (t, 4H, J = 4.6 Hz), 2.88 (t, 2H, J = 5.8 Hz),3.75 (t, 4H, J = 4.6 Hz), 4.18 (t, 2H, J = 5.8 Hz), 6.52-6.54 (m, 1H),6.61 (s, 1H), 6.90 (d, 1H, J = 7.7 Hz), 6.94-6.98 (m, 1H), 7.06 (d, 1H,J = 16.3 Hz), 7.13 (d, 1H, J = 16.7 Hz), 7.18-7.25 (m, 3H), 7.31-7.34(m, 1H), 7.42-7.47 (m, 2H), 7.55 (dd, 1H, J = 1.6 Hz, 7.7 Hz), 7.60 (d,1H, J = 8.2 Hz), 8.15 (brs, 1H) MS (EI) m/z 440 (M⁺).

TABLE 35 53-1

  1H NMR (δ, CDCl₃): 2.56-2.62 (m, 4H), 2.81-2.84 (m, 2H), 3.72-3.76 (m,4H), 4.13-4.17 (m, 2H), 5.84 (s, 1H), 6.56-6.59 (m, 1H), 6.60 (d, 1H, J= 15.9 Hz), 6.65 (d, 1H, J = 15.9 Hz), 6.92 (dd, 1H, J = 2.45 Hz, 8.1Hz), 7.08-7.10 (m, 1H), 7.15 (d, 1H, J = 7.85 Hz), 7.27-7.32 (m, 2H),7.39-7.42 (m, 1H), 7.57 (s, 1H), 7.60 (d, 1H, J = 15.9 Hz), 7.64 (d, 1H,J = 8.1 Hz), 7.81 (d, 1H, J = 15.9 Hz), 8.32 (brs, 1H), 15.97 (brs, 1H)MS (EI) m/z 444 (M⁺). 53-2

  1H NMR (δ, CDCl₃): 2.68 (brs, 4H), 2.90 (brs, 2H), 3.79 (brs, 4H),4.21 (brs, 2H), 6.54-6.56 (m, 1H), 6.63 (s, 1H), 6.82-6.85 (m, 1H), 7.02(d, 1H, J = 16.3 Hz), 7.04-7.06 (m, 3H), 7.10 (d, 1H, J = 7.7 Hz), 7.19(d, 1H, J = 16.3 Hz), 7.22-7.24 (m, 1H), 7.25-7.29 (m, 1H), 7.33 (dd,1H, J = 1.4 Hz, 8.3 Hz), 7.48 (s, 1H), 7.62 (d, 1H, J = 8.3 Hz), 8.19(brs, 1H) MS (EI) m/z 440 (M⁺). 54-1

  MS (EI) m/z 466 (M⁺). 54-2

  1H NMR (δ, CDCl₃): 3.29 (t, 2H, J = 6.7 Hz), 3.86 (s, 3H), 4.41 (t,2H, J = 6.7 Hz), 6.47 (d, 1H, J = 2.3 Hz), 6.52-6.56 (m, 2H), 6.62 (s,1H), 6.96 (d, 1H, J = 16.5 Hz), 7.05 (d, 1H, J = 16.5 Hz), 7.15-7.23 (m,3H), 7.24-7.28 (m, 1H), 7.30 (d, 1H, J = 16.5 Hz), 7.33 (dd, 1H, J = 1.4Hz, 8.3 Hz), 7.43 (d, 1H, J = 8.3 Hz), 7.49 (s, 1H), 7.61 (d, 1H, J =8.7 Hz), 7.61-7.66 (m, 1H), 8.17 (brs, 1H), 8.56-8.59 (m, 1H) MS (EI)m/z 462 (M⁺).

TABLE 36 55-1

  1H NMR (δ, CDCl₃): 2.15 (s, 3H), 4.25-4.30 (m, 4H), 5.61 (s, 1H), 6.31(d, 1H, J = 15.7 Hz), 6.86 (d, 1H, J = 8.3 Hz), 7.02 (dd, 1H, J = 2.0Hz, 8.3 Hz), 7.05 (d, 1H, J = 2.0 Hz), 7.48 (d, 1H, J = 15.7 Hz), 15.41(brs, 1H) 55-2

  MS (EI) m/z 493 (M⁺). 55-3

  1H NMR (δ, CDCl₃): 2.58-2.61 (m, 4H), 2.81 (t, 2H, J = 5.7 Hz),3.73-3.76 (m, 4H), 3.86 (s, 3H), 4.14 (t, 2H, J = 5.7 Hz), 4.26-4.27 (m,4H), 6.48-6.51 (m, 2H), 6.58 (s, 1H), 6.84 (d, 1H, J = 8.3 Hz), 6.89 (d,1H, J = 16.5 Hz), 6.93-6.99 (m, 3H), 7.01 (d, 1H, J = 1.8 Hz), 7.29 (d,1H, J = 16.5 Hz), 7.43 (d, 1H, J = 8.7 Hz) MS (EI) m/z 489 (M⁺). 56-1

  1H NMR (δ, CDCl₃): 2.56-2.60 (m, 8H), 2.81 (t, 4H, J = 5.7 Hz),3.72-3.75 (m, 8H), 3.88 (s, 6H), 4.15 (t, 4H, J = 5.7 Hz), 5.79 (s, 1H),6.48 (d, 2H, J = 2.5 Hz), 6.51 (dd, 2H, J = 2.5 Hz, 8.5 Hz), 6.62 (d,2H, J = 16.0 Hz), 7.47 (d, 2H, J = 8.5 Hz), 7.77 (d, 2H, J = 16.0 Hz),16.13 (brs, 1H). MS (EI) m/z 594 (M⁺). 56-2

  1H NMR (δ, CDCl₃): 2.57-2.61 (m, 8H), 2.81 (t, 4H, J = 5.7 Hz),3.73-3.76 (m, 8H), 3.86 (s, 6H), 4.14 (t, 4H, J = 5.7 Hz), 6.47-6.52 (m,4H), 6.61 (s, 1H), 6.97 (d, 2H, J = 16.5 Hz), 7.30 (d, 2H, J = 16.5 Hz),7.44 (d, 2H, J = 8.3 Hz) MS (EI) m/z 590 (M⁺).

TABLE 37 57-1

  MS (EI) m/z 436 (M⁺). 57-2

  1H NMR (δ, CDCl₃): 3.81 (s, 3H), 5.23 (s, 2H), 6.62 (s, 1H), 6.80 (s,1H), 6.89 (d, 1H, J = 16.4 Hz), 6.97 (d, 2H, J = 8.7 Hz), 7.04 (d, 1H, J= 16.4 Hz), 7.07-7.12 (m, 1H), 7.10 (d, 1H, J = 16.3 Hz), 7.17 (d, 1H, J= 16.3 Hz), 7.18-7.30 (m, 3H), 7.41 (d, 2H, J = 8.7 Hz), 7.52 (d, 1H, J= 7.9 Hz), 7.58 (d, 1H, J = 7.8 Hz), 7.70-7.74 (m, 1H), 8.61 (d, 1H, J =4.4 Hz) MS (EI) m/z 432 (M⁺). 58-1

  MS (EI) m/z 466 (M⁺). 58-2

  1H NMR (δ, Acetone-d₆): 3.84 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H),6.44-6.46 (m, 1H), 6.65-6.68 (m, 2H), 6.74 (d, 1H, J = 2.3 Hz),7.04-7.09 (m, 2H), 7.21 (d, 1H, J = 3.2 Hz), 7.29-7.34 (m, 2H),7.36-7.41 (m, 2H), 7.46 (dd, 1H, J = 1.4, 8.7 Hz), 7.53 (d, 1H, J = 8.3Hz), 7.56-7.58 (m, 1H), 7.70-7.72 (m, 1H), 7.80-7.84 (m, 1H), 8.58-8.60(m, 1H), 11.93 (brs, 1H) MS (EI) m/z 462 (M⁺).

TABLE 38 59-1

  1H NMR (δ, CDCl₃): 2.45 (s, 3H), 3.83 (s, 3H), 5.23 (s, 2H), 5.82 (s,1H), 6.45-6.50 (m, 2H), 6.67 (d, 1H, J = 15.8 Hz), 6.84-6.87 (m, 2H),7.13 (d, 1H, J = 3.0 Hz), 7.22-7.27 (m, 1H), 7.37-7.40 (m, 1H),7.48-7.52 (m, 2H), 7.56-7.63 (m, 2H), 7.70-7.74 (m, 1H), 7.83 (d, 1H, J= 15.8 Hz), 7.89 (d, 1H, J = 15.8 Hz), 8.60-8.62 (m, 1H) MS (EI) m/z 450(M⁺). 59-2

  1H NMR (δ, CDCl₃): 2.41 (s, 3H), 3.80 (s, 3H), 5.22 (s, 2H), 6.46-6.48(m, 1H), 6.63 (s, 1H), 6.82-6.87 (m, 3H), 7.06 (d, 1H, J = 3.1 Hz), 7.07(d, 1H, J = 16.5 Hz), 7.21-7.28 (m, 3H), 7.31-7.33 (m, 1H), 7.40-7.42(m, 1H), 7.50-7.54 (m, 2H), 7.59 (d, 1H, J = 8.2 Hz), 7.70-7.74 (m, 1H),8.60-8.62 (m, 1H) MS (EI) m/z 446 (M⁺).

Pharmacological Test Example 1 Determination of Tau AggregationInhibitory Activity

Recombinant three-repeat microtubule-binding domain (3R-MBD) of tauprotein was expressed in E. coli and was purified and used for theexperiment. The purified tau solution was diluted with a 50 mM Tris-HClbuffer (pH 7.6) to a final concentration of 10 μM. The test compoundswere prepared using dimethylsulfoxide (hereinafter also referred to asDMSO) at 20-fold of their final concentrations and added to the tausolution so that the DMSO concentration would be 5%. To this solution,heparin was added so that the final concentration would be 10 μM and theplate was left to stand at 37° C. for 16 hours. Thioflavin T was addedto the plate so that the concentration would be 10 μM and thefluorescence intensity was measured with a fluorescence plate reader(PerkinElmer, Inc.)(excitation wavelength: 440 nm; fluorescencewavelength: 486 nm).

The final concentration of each compound at the time of measurement wasset at 0.1, 0.3, 1, 3, and 10 μM. The sample to which only DMSO wasadded was used as a negative control and its fluorescence intensity wastaken as 0% inhibitory activity to determine the 50% inhibitoryconcentration (IC₅₀) of each compound. The results are shown in Table39. Table 39 also shows the calculated maximum inhibition (%) of thecompounds that exhibited particularly high maximum inhibition (%) at theconcentrations used for the determination of the tau aggregationinhibitory activity.

TABLE 39 Maximum Compound IC₅₀ (μM) inhibition (%) Example 16-2 0.6  —Example 17-2 0.65 — Example 19-4 0.51 — Example 20-3 0.55 89 Example21-2 — 89 Example 22-2 0.66 90 Example 23-2 0.59 92 Example 25-2 0.84 —Example 27-3 — 91 Example 28-2 — 93 Example 32-5 0.64 90 Example 42-20.83 — Example 43-2 — 92 Example 53-2 0.84 —

As is apparent from Table 39, some of the compounds of the presentinvention exhibited a particularly high tau aggregation inhibitoryactivity. The compounds that exhibited high maximum inhibition areexpected to have improved therapeutic effects and are thus morepreferred.

Pharmacological Test Example 2 Determination of β-secretase InhibitoryActivity

The β-secretase inhibitory activity was measured with BACE-1 FRET assayKit (Invitrogen). The test compounds were prepared using DMSO at 30-foldof their final concentrations and added to an assay buffer so that theDMSO concentration would be 10%. To each of the solutions, equal volumesof a human recombinant β-secretase (1 U/mL) and a fluorescent substratepeptide (750 nM), each dissolved in an assay buffer, were added and thesolutions were left to stand for 1 hour. The fluorescence intensity wasmeasured with a fluorescence plate reader (excitation wavelength: 545nm; fluorescence wavelength: 590 nm).

The final concentration of each compound at the time of measurement wasset at 0.1, 0.3, 1, 3, and 10 μM, at 0.3, 1, 3, 10, and 30 μM, or at 1,3, 10, 30, and 100 μM. The sample to which only DMSO was added was usedas a negative control and its fluorescence intensity was taken as 0%inhibitory activity to determine the 50% inhibitory concentration (IC₅₀)of each compound for the evaluation of β-secretase inhibitory activityof each compound. The fluorescent substrate peptide had the amino acidsequence of Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Lys-Arg, in which the Serresidue at position 1 was labeled with a fluorescent donor (Cy3) and theLys at position 9 was labeled with a fluorescence quencher (Cy5Q).

The compounds of the present invention exhibited a high β-secretaseinhibitory activity.

Pharmacological Test Example 3 Determination of Aβ AggregationInhibitory Activity

Aβ 1-42 (Peptide Institute, Inc.) was dissolved in 0.1% ammonia water sothat the concentration would be 0.5 mM, and then diluted with PBS to 20μM. The test compounds were prepared using DMSO at 100-fold of theirfinal concentrations and then diluted with PBS so that the DMSOconcentration would be 2%. The Aβ solution and each of the test compoundsolutions were mixed at an equivalent ratio and the mixtures were leftto stand at 37° C. for 24 hours. To each of the mixtures, an equalvolume of a thioflavin T solution adjusted with a 100 mM Tris-glycinebuffer (pH 8.5) to 6 μM was added. The fluorescence intensity wasmeasured with a fluorescence plate reader (excitation wavelength: 440nm; fluorescence wavelength: 486 nm).

The final concentration of each compound at the time of measurement wasset at 0.1, 0.3, 1, 3, and 10 μM or at 2, 4, 8, and 16 μM. The sample towhich only DMSO was added was used as a negative control and itsfluorescence intensity was taken as 0% inhibitory activity. With the useof the fluorescence intensity of the control taken as 0% inhibitoryactivity, the 50% inhibitory concentration (IC₅₀) of each compound wascalculated to evaluate the Aβ aggregation inhibitory activity of eachcompound.

The compounds of the present invention exhibited a high Aβ aggregationinhibitory activity.

Pharmacological Test Example 4 Concentration Measurement in Brain afterOral Administration

Each of the compounds of the present invention shown in Tables 40 and 41and the compound of Example 2 of JP 2012-229208 A was orallyadministered to ICR mice (male, 7 weeks old) in a single dose of 5mg/kg. At 3, 6 and 9 hours after the administration, 1, 3, 6 and 9 hoursafter the administration, or 1, 3, 6, 9 and 24 hours after theadministration, the mice were subjected to perfusion by infusingphysiological saline into the heart under inhalational anesthesia withisoflurane, and the whole brain was harvested. Physiological saline wasadded to the harvested brain in an amount equal to twice the wet weightof the brain and the brain was homogenized. Then, an equal volume ofmethanol was added thereto, and the mixture was deproteinized. Theconcentration of each compound in the sample was measured by LC/MS/MS.The test results are shown in Tables 40 and 41.

TABLE 40 AUC_(0-9 h) in brain Compound (ng · hr/g-tissue) Example 22-2458 Example 44-2 869 JP 2012-229208 A, Example 2 224

TABLE 41 AUC_(0-24 h) in brain Compound (ng · hr/g-tissue) Example 14-224639  Example 18-2 9781 Example 19-4 3499 Example 20-3 5306 Example27-3 1302 JP 2012-229208 A, Example 2 645 to 677

INDUSTRIAL APPLICABILITY

The compound of the present invention is useful as a prophylactic drug,a therapeutic drug, and the like for Alzheimer's disease and thereforethe present invention can be applied to industrial fields such aspharmaceutical industry.

The invention claimed is:
 1. A compound represented by the followinggeneral formula (I):

[wherein R¹ represents a hydrogen atom, a halogen atom, a hydroxy group,a nitro group, an amino group, a cyano group, a C₁₋₆ alkyl groupoptionally having one or more substituents, a C₁₋₆ alkoxy groupoptionally having one or more substituents, a mono- or di(C₁₋₆alkyl)amino group optionally having one or more substituents, a C₁₋₆alkylthio group optionally having one or more substituents, a C₁₋₆alkylsulfonyl group optionally having one or more substituents, a C₁₋₆acyl group optionally having one or more substituents, a C₁₋₆ acylaminogroup optionally having one or more substituents, a C₂₋₆ alkenyl groupoptionally having one or more substituents, a C₂₋₆ alkenyloxy groupoptionally having one or more substituents, a mono- or di(C₂₋₆alkenyl)amino group optionally having one or more substituents, a C₂₋₆alkenylthio group optionally having one or more substituents, or acarbamoyl group optionally having one or more substituents; R²represents a group represented by the following general formula (II):

(wherein m and n each represent an integer of 0 or 1, A represents —O—,—NH—, —S—, —SO— or —SO₂—, Y represents a C₁₋₆ alkylene group, a C₂₋₆alkenylene group or a C₂₋₆ alkynylene group, and R³ represents anitrogen-containing heterocyclic group optionally having one or moresubstituents, a C₁₋₆ alkoxy group optionally having one or moresubstituents, a mono- or di(C₁₋₆ alkyl)amino group optionally having oneor more substituents, a mono- or di(C₂₋₆ alkenyl)amino group optionallyhaving one or more substituents, or a carbamoyl group optionally havingone or more substituents); R¹ and R² may be joined to form a ringtogether with the benzene ring; and Ar represents a homocyclic orheterocyclic group optionally having one or more substituents], or asalt thereof.
 2. The compound according to claim 1 or a salt thereof,wherein m is 1 and A is —O—.
 3. The compound according to claim 2 or asalt thereof, wherein R² is a morpholinomethoxy group, amorpholinoethoxy group, a pyridylmethoxy group, a pyridylethoxy group, a2-pyrrolidinoethoxy group, a 2-piperidinoethoxy group, a2-(4-(substituted)piperazino)ethoxy group, or a2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy group.
 4. The compound accordingto claim 3 or a salt thereof, wherein R² is a morpholinoethoxy group. 5.The compound according to claim 1 or a salt thereof, wherein R² is amorpholinomethyl group, a (4-(substituted)piperazino)methyl group, a(1,1-dioxo-1,4-thiazinan-4-yl)methyl group, a piperidinomethyl group, apyrrolidinomethyl group, a 2-morpholinoethyl group, a2-(4-(substituted)piperazino)ethyl group, a2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl group, a 2-piperidinoethyl group,a 2-pyrrolidinoethyl group, or a 2-morpholinoethanesulfonyl group. 6.The compound according to claim 1 or a salt thereof, wherein R² is a4-(substituted)piperazino group or a 4-(substituted)-1,4-diazepanogroup, with the exception of the case where Ar is a homocyclic groupoptionally having a substituent.
 7. The compound according to claim 1 ora salt thereof, wherein Ar is a bicyclic group having a benzene skeletonand optionally having one or more substituents.
 8. The compoundaccording to claim 7 or a salt thereof, wherein the bicyclic grouphaving a benzene skeleton is a 1,3-benzodioxole group, a1,4-benzodioxan-5-yl group, a 1,4-benzodioxan-6-yl group, a1,4-benzodioxin-2-yl group, a quinolino group, or an indolyl group. 9.The compound according to claim 1 or a salt thereof, wherein Ar is aphenyl group optionally having one or more substituents, a pyrrolylgroup optionally having one or more substituents, a pyridyl groupoptionally having one or more substituents, a pyrazyl group optionallyhaving one or more substituents, an imidazolyl group optionally havingone or more substituents, or a furyl group optionally having one or moresubstituents.
 10. The compound according to claim 6 or a salt thereof,wherein Ar is a pyrrolyl group optionally having one or moresubstituents, a pyridyl group optionally having one or moresubstituents, a pyrazyl group optionally having one or moresubstituents, an imidazolyl group optionally having one or moresubstituents, or a furyl group optionally having one or moresubstituents.
 11. The compound according to claim 1 or a salt thereof,wherein Ar is represented by the following general formula (III):

(wherein R¹′ represents a hydrogen atom, a halogen atom, a hydroxygroup, a nitro group, an amino group, a cyano group, a C₁₋₆ alkyl groupoptionally having one or more substituents, a C₁₋₆ alkoxy groupoptionally having one or more substituents, a mono- or di(C₁₋₆alkyl)amino group optionally having one or more substituents, a C₁₋₆alkylthio group optionally having one or more substituents, a C₁₋₆alkylsulfonyl group optionally having one or more substituents, a C₁₋₆acyl group optionally having one or more substituents, a C₁₋₆ acylaminogroup optionally having one or more substituents, a C₂₋₆ alkenyl groupoptionally having one or more substituents, a C₂₋₆ alkenyloxy groupoptionally having one or more substituents, a mono- or di(C₂₋₆alkenyl)amino group optionally having one or more substituents, a C₂₋₆alkenylthio group optionally having one or more substituents, or acarbamoyl group optionally having one or more substituents; R²′represents a group represented by the following general formula (IV):

(wherein m′ and n′ each represent an integer of 0 or 1, A′ represents—O—, —NH—, —S—, —SO— or —SO₂—, Y′ represents a C₁₋₆ alkylene group, aC₂₋₆ alkenylene group or a C₂₋₆ alkynylene group, and R³′ represents anitrogen-containing heterocyclic group optionally having one or moresubstituents, a C₁₋₆ alkoxy group optionally having one or moresubstituents, a mono- or di(C₁₋₆ alkyl)amino group optionally having oneor more substituents, a mono- or di(C₂₋₆ alkenyl)amino group optionallyhaving one or more substituents, or a carbamoyl group optionally havingone or more substituents), and R¹′ and R²′ may form a ring together withthe benzene ring).
 12. A tau aggregation inhibitor comprising thecompound according to claim 1 or a salt thereof as an active ingredient.13. A β-secretase inhibitor comprising the compound according to claim 1or a salt thereof as an active ingredient.
 14. An Aβ aggregationinhibitor comprising the compound according to claim 1 or a salt thereofas an active ingredient.
 15. A pharmaceutical composition comprising thecompound according to claim 1 or a salt thereof as an active ingredient.16. An oral or parenteral preparation comprising the compound accordingto claim 1 or a salt thereof and one or more pharmacologicallyacceptable carriers.